Inhibitors of GSK-3 and uses thereof

ABSTRACT

The present invention relates to compounds of formula I that are useful as GSK-3 inhibitors. The invention also relates to methods of using compounds of formula I or pharmaceutical compositions comprising compounds of formula I to inhibit GSK-3 activity. The invention further provides methods of utilizing these compounds and pharmaceutical compositions in the treatment and prevention of various disorders, such as diabetes and Alzheimer&#39;s disease. The invention also relates to methods for inhibiting Aurora-2 activity and for treating or preventing Aurora-2-mediated diseases using compounds of formula I or pharmaceutical compositions comprising compounds of formula I. The invention also relates to methods for inhibiting cyclin-dependent kinase-2 activity and for treating or preventing inhibiting cyclin-dependent kinase-2-mediated diseases using compounds of formula I or pharmaceutical compositions comprising compounds of formula I.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional PatentApplication 60/309,838, filed Aug. 1, 2002, the content of which isincorporated by reference.

TECHNICAL FIELD OF INVENTION

[0002] The present invention relates to inhibitors of glycogen synthasekinase-3 (GSK-3), a serine/threonine protein kinase. The inventionprovides methods of using these compounds or pharmaceutical compositionscomprising these compounds to inhibit GSK-3 activity. The inventionfurther provides methods of utilizing these compounds or pharmaceuticalcompositions in the treatment and prevention of various disorders, suchas diabetes and Alzheimer's disease. The invention also relates tomethods for inhibiting Aurora-2 protein kinase or cyclin-dependentkinase-2, using these compounds or pharmaceutical compositions.

BACKGROUND OF THE INVENTION

[0003] The search for new therapeutic agents has been greatly aided inrecent years by a better understanding of the structure of enzymes andother biomolecules associated with target diseases. One important classof enzymes that has been the subject of extensive study is proteinkinases.

[0004] Protein kinases mediate intracellular signal transduction. Theydo this by effecting a phosphoryl transfer from a nucleosidetriphosphate to a protein acceptor that is involved in a signalingpathway. There are a number of kinases and pathways through whichextracellular and other stimuli cause a variety of cellular responses tooccur inside the cell. Examples of such stimuli include environmentaland chemical stress signals (e.g., osmotic shock, heat shock,ultraviolet radiation, bacterial endotoxin, and H₂O₂), cytokines (e.g.,interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α)), and growthfactors (e.g., granulocyte macrophage-colony-stimulating factor(GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulusmay affect one or more cellular responses related to cell growth,migration, differentiation, secretion of hormones, activation oftranscription factors, muscle contraction, glucose metabolism, controlof protein synthesis and regulation of cell cycle.

[0005] Many disease states are associated with abnormal cellularresponses triggered by protein kinase-mediated events. These diseasesinclude autoimmune diseases, inflammatory diseases, metabolic diseases,neurological and neurodegenerative diseases, cancer, cardiovasculardiseases, allergies and asthma, Alzheimer's disease and hormone-relateddiseases. Accordingly, there has been a substantial effort in medicinalchemistry to find protein kinase inhibitors that are effective astherapeutic agents. A challenge has been to find protein kinaseinhibitors that act in a selective manner. Since there are numerousprotein kinases that are involved in a variety of cellular responses,non-selective inhibitors may lead to unwanted side effects.

[0006] Glycogen synthase kinase-3 (GSK-3) is a serine/threonine proteinkinase comprised of α and β isoforms that are each encoded by distinctgenes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); and Kimand Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 hasbeen implicated in various diseases including diabetes, Alzheimer'sdisease, CNS disorders such as manic depressive disorder andneurodegenerative diseases, and cardiomyocete hypertrophy [see, e.g., WO99/65897; WO 00/38675; and Haq et al., J. Cell Biol. (2000) 151, 117].These diseases may be caused by, or may result in, the abnormaloperation of certain cell signaling pathways in which GSK-3 plays arole.

[0007] GSK-3 has been found to phosphorylate and modulate the activityof a number of regulatory proteins. These include glycogen synthase,which is the rate-limiting enzyme required for glycogen synthesis, themicrotubule-associated protein Tau, the gene transcription factorβ-catenin, the translation initiation factor e1F-2B, as well as ATPcitrate lyase, axin, heat shock factor-1, c-Jun, c-myc, c-myb, CREB, andCEPBα. These diverse targets implicate GSK-3 in many aspects of cellularmetabolism, proliferation, differentiation and development.

[0008] In a GSK-3 mediated pathway that is relevant for the treatment oftype II diabetes, insulin-induced signaling leads to cellular glucoseuptake and glycogen synthesis. GSK-3 is a negative regulator of theinsulin-induced signal in this pathway. Normally, the presence ofinsulin causes inhibition of GSK-3-mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93,8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen,Biochem. Soc. Trans., 21, 555-567 (1993); and Massillon et al., BiochemJ. 299, 123-128 (1994)]. However, where the insulin response is impairedin a diabetic patient, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and chronic effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentiallyuseful for treating diabetic patients suffering from an impairedresponse to insulin.

[0009] GSK-3 activity has also been associated with Alzheimer's disease.This disease is characterized by the presence of the well-knownβ-amyloid peptide and the formation of intracellular neurofibrillarytangles. The neurofibrillary tangles contain hyperphosphorylated Tauprotein, in which Tau is phosphorylated on abnormal sites. GSK-3 hasbeen shown to phosphorylate these abnormal sites in cell and animalmodels. Furthermore, inhibition of GSK-3 has been shown to preventhyperphosphorylation of Tau in cells [Lovestone et al., Current Biology4, 1077-86 (1994); and Brownlees et al., Neuroreport 8, 3251-55 (1997)].Therefore, it is believed that GSK-3 activity may promote generation ofneurofibrillary tangles and progression of Alzheimer's disease.

[0010] Another substrate of GSK-3 is β-catenin, which is degradatedafter phosphorylation by GSK-3. Reduced levels of β-catenin have beenreported in schizophrenic patients and have also been associated withother diseases related to increase in neuronal cell death [Zhong et al.,Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993);Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997); and Smith et al.,Bio-org. Med. Chem. 11, 635-639 (2001)].

[0011] Small molecule inhibitors of GSK-3 have recently been reported[WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)]; however,there is a continued need to find new therapeutic agents to treat humandiseases. The protein kinase GSK-3, in particular GSK-3β, is anespecially attractive target for the discovery of new therapeutics dueto its important role in diabetes, Alzheimer's disease and otherdiseases.

[0012] Aurora-2 is another serine/threonine protein kinase that has beenimplicated in human cancer, such as colon, breast and other solidtumors. This kinase is believed to be involved in proteinphosphorylation events that regulate the cell cycle. Specifically,Aurora-2 may play a role in controlling the accurate segregation ofchromosomes during mitosis. Misregulation of the cell cycle can lead tocellular proliferation and other abnormalities. In human colon cancertissue, the Aurora-2 protein has been found to be overexpressed[Bischoff et al., EMBO J., 17, 3052-3065 (1998); Schumacher et al., J.Cell Biol., 143, 1635-1646 (1998); and Kimura et al., J. Biol. Chem.,272, 13766-13771 (1997)].

[0013] Cyclin-dependent kinases (CDKs) inhibitors have been described asanticancer agents [Fischer, P. M. and Lane, D. P., Current MedicinalChemistry, 7, 1213-1245 (2000); Mani, S., Wang, C., Wu, K., Francis, R.and Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000); and Fry, D.W. and Garrett, M. D., Current Opinion in Oncologic, Endocrine &Metabolic Investigational Drugs, 2, 40-59 (2000)]. Although some CDK-2inhibitors have been disclosed, it would be desirable to have otherCDK-2 inhibitors for treating human diseases.

[0014] Therefore, there is a need to inhibit protein kinases,particularly glycogen synthase kinases, Aurora and cyclin-dependentkinases, more particularly GSK-3, Aurora-2 and CDK-2, for treatment ofhuman diseases.

SUMMARY OF THE INVENTION

[0015] The present invention provides methods for effectively inhibitingprotein kinases, particularly glycogen synthase kinases, Aurora andcyclin-dependent kinases, and more particularly GSK-3, Aurora-2 andCDK-2, utilizing compounds and pharmaceutical compositions describedherein. These compounds have the general formula I:

[0016] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0017] R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R;

[0018] R₂ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl; orheteroaryl; wherein said alkyl, carbocyclyl, or heterocyclyl isoptionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR, ═NN(R)COR, ═NNRCO₂R,═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, or —NRS(O)₂R;

[0019] X is O, S or —NH;

[0020] Y is N or CH;

[0021] each R is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′,═O, ═S, ═NN(R′)₂, ═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′,═N—CN, or ═NR′; and wherein said aryl or heteroaryl is optionallysubstituted with one to four substituents independently selected fromhalo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂,—N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂,—S(O)R′, or —N(R′)S(O)₂R′;

[0022] each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″,—CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN (R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR—, —NO₂, —CN, —N(R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and

[0023] each R″ is independently selected from H or alkyl.

[0024] In one embodiment, the invention provides compositions comprisingcompounds of formula I. The compounds and compositions of the presentinvention may be utilized in methods for treating or preventing avariety of GSK-3 mediated disorders, such as autoimmune diseases,inflammatory diseases, metabolic, neurological and neurodegenerativediseases, cardiovasclular diseases, allergy, asthma, diabetes,Alzheimer's disease, Huntington's Disease, Parkinson's Disease,AIDS-associated dementia, amyotrophic lateral sclerosis (AML, LouGehrig's Disease), multiple sclerosis (MS), schizophrenia, cardiomyocytehypertrophy, reperfusion/ischemia, and baldness.

[0025] The compounds and compositions of this invention are also usefulin methods for enhancing glycogen synthesis and/or lowering blood levelsof glucose and therefore are especially useful for diabetic patients.These compounds and compositions are also useful in methods forinhibiting the production of hyperphosphorylated Tau protein, which isuseful in halting or slowing the progression of Alzheimer's disease.Another embodiment of this invention relates to a method for inhibitingthe phosphorylation of β-catenin, which is useful for treatingschizophrenia.

[0026] In another embodiment, the invention provides methods forpreparing pharmaceutical compositions comprising compounds of formula I.

[0027] In yet another embodiment, the invention provides methods foreffectively inhibiting Aurora-2 activity and for treating or preventingAurora-2-mediated conditions utilizing compounds of formula I andpharmaceutical compositions thereof.

[0028] In another embodiment, the invention provides methods foreffectively inhibiting CDK-2 activity and for treating or preventingCDK-2-mediated conditions utilizing compounds of formula I andpharmaceutical compositions thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0029] The following abbreviations are used throughout thespecifications (including in chemical formulae):

[0030] iPr=isopropyl

[0031] t-Bu or tBu=tert-butyl

[0032] Et=ethyl

[0033] Me=methyl

[0034] Cbz=benzyloxycarbonyl

[0035] DEAD=diethyl azodicarboxylate

[0036] Ph=phenyl

[0037] Bn=benzyl

[0038] DMF=N,N-dimethylformamide THF=tetrahydrofuran

[0039] DCM=dichloromethane

[0040] dba=dibenzylidene-acetone

[0041] BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

[0042] DMSO=dimethylsulfoxide

[0043] HPLC=high pressure liquid chromatography

[0044] As used herein, the following definitions shall apply unlessotherwise indicated. Also, combinations of substituents or variables arepermissible only if such combinations result in stable compounds.

[0045] The term “alkyl” as used herein, alone or in combination with anyother term, refers to straight chain or branched C₁-C₁₂ hydrocarbonsthat are completely saturated or that contain one or more units ofunsaturation. The term “alkyl” includes hydrocarbons that contain atleast one carbon-carbon double bond (i.e., alkenyl) or at least onecarbon-carbon triple bond (i.e., alkynyl). Preferably, alkyl radicalscontain one to six carbon atoms. Examples of alkyl radicals include, butare not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,i-butyl, t-butyl, pentyl, isoamyl, n-hexyl, ethenyl, E- and Z-propenyl,isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl,E- and Z-hexenyl, E,E-, E,Z-, Z,E- and Z,Z-hexadienyl, ethynyl,propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like. Theterm “alkoxy” refers to —O-alkyl.

[0046] The term “carbocylyl” or “carbocyclic”, alone or in combinationwith any other term, refers to monocyclic or polycyclic non-aromatichydrocarbon ring systems, which may contain a specified number of carbonatoms, preferably from 3 to 14 carbon atoms, which are completelysaturated or which contain one or more units of unsaturation. Acarbocyclic ring system may be monocyclic, bicyclic or tricyclic. Acarbocylyl ring may be fused to another ring, such as an aryl ring oranother carbocyclic ring, where the radical or point of attachment is onthe carbocylyl ring. Five- to seven-membered monocyclic and nine- toeleven-membered bicyclic carbocyclic ring systems are preferred.Examples of carbocyclic rings include cyclohexyl, cyclopentyl,cyclobutyl, cyclopropyl, cyclohexenyl, cyclopentenyl, indanyl,tetrahydronaphthyl and the like. The term “carbocyclic” or “carbocylyl”also encompasses hybrids of alkyl and carbocyclic groups, such as(cycloalkyl)alkyl.

[0047] The term “halogen” or “halo” means F, Cl, Br, or I.

[0048] The term “heteroatom” means N, O, or S and shall include anyoxidized form of nitrogen and sulfur, such as N(O), S(O), S(O)₂ and thequaternized form of any basic nitrogen.

[0049] The term “heterocyclic” or “heterocyclyl” refers to non-aromaticsaturated or unsaturated monocyclic or polycyclic ring systemscontaining one or more heteroatoms and with a ring size of three tofourteen. One having ordinary skill in the art will recognize that themaximum number of heteroatoms in a stable, chemically feasibleheterocyclic ring is determined by the size of the ring, degree ofunsaturation, and valence. In general, a heterocyclic ring may have oneto four heteroatoms so long as the heterocyclic ring is chemicallyfeasible and stable and may be fused to another ring, such as acarbocyclic, aryl or heteroaryl ring, or to another heterocyclic ring. Aheterocyclic ring system may be monocyclic, bicyclic or tricyclic. Five-to seven-membered monocyclic and nine- to eleven-membered bicyclicheterocyclic ring systems are preferred. The term “heterocyclylalkyl”refers to an alkyl group substituted by a heterocyclyl. Also includedwithin the scope of the term “heterocyclic” or “heterocyclyl”, as usedherein, are radicals wherein one or more carbocyclic rings are fused toa heteroaryl.

[0050] Examples of heterocyclic rings include, but are not limited to,3-1H-benzimidazol-2-one, 3-1H-alkyl-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl,benzoxane, benzotriazol-1-yl, benzopyrrolidine, benzopiperidine,benzoxolane, benzothiolane, benzothiane, aziranyl, oxiranyl, azetidinyl,pyrrolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl,pyrazolidinyl, pyranyl, dioxanyl, dithianyl, trithianyl, quinuclidinyl,oxepanyl, and thiepanyl.

[0051] The term “aryl”, alone or in combination with other terms, refersto monocyclic or polycyclic aromatic carbon ring systems having five tofourteen members. Five- to seven-membered monocyclic and nine- toeleven-membered bicyclic aryl ring systems are preferred. Examples ofaryl groups include, but are not limited to, phenyl (Ph), 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scopeof the term “laryl”, as it is used herein, is a group in which an arylis fused to one or more aryl or carbocyclic rings, such as in anindanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical orpoint of attachment is on the aryl. The term “aralkyl” refers to analkyl group substituted by an aryl. Examples of aralkyl groups include,but are not limited to, benzyl and phenethyl.

[0052] The term “heteroaryl”, alone or in combination with any otherterm, refers to monocyclic or polycyclic heterocyclic aromatic ringsystems having five to fourteen members. One having ordinary skill inthe art will recognize that the maximum number of heteroatoms in astable, chemically feasible hetearoaryl ring is determined by the sizeof the ring and valence. Five- to seven-membered monocyclic and nine- toeleven-membered bicyclic heteroaryl ring systems are preferred. The term“heteroaralkyl” refers to an alkyl group substituted by a heteroaryl. Ingeneral, a heteroaryl ring may have one to four heteroatoms. Heteroarylgroups include, without limitation, 2-furanyl, 3-furanyl, N-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl,2-thienyl, and 3-thienyl.

[0053] Also included within the scope of the term “heteroaryl”, as usedherein, are radicals wherein one or more heteroaryl rings are fused to aheteroaryl, an aryl, a carbocyclic or a heterocyclic ring, where theradical or point of attachment is on the heteroaryl. Examples of suchfused polycyclic heteroaryl ring systems include, benzimidazolyl,benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazolyl,benzoxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl,benzoisoxazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[3,4-d]pyrimidinyl and the like.

[0054] Guided by this specification, the selection of suitablesubstituents of radicals defined herein is within the knowledge of oneskilled in the art.

[0055] A substitutable nitrogen on a heteroaryl or a non-aromaticheterocyclic ring is optionally substituted. Suitable substituents onthe nitrogen include R⁰, COR⁰, S(O)₂R⁰, S(O)₂-aryl such as phenyl, andCO₂R⁰, wherein R⁰ is H or alkyl.

[0056] The term “chemically feasible or stable”, as used herein, refersto a compound structure that is sufficiently stable to allow manufactureand administration to a patient by methods known in the art. Typically,such compounds are stable at a temperature of 40° C. or less, in theabsence of moisture or other chemically reactive conditions, for atleast one week.

[0057] One object of the instant invention is to provide compoundshaving formula (I):

[0058] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0059] R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N-OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R;

[0060] R₂ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl; orheteroaryl; wherein said alkyl, carbocyclyl, or heterocyclyl isoptionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR, ═NN(R)COR, ═NNRCO₂R,═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, or —NRS(O)₂R;

[0061] X is O, S or —NH;

[0062] Y is N or CH;

[0063] each R is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R—, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′,═O, ═S, ═NN(R′)₂, ═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′,═N—CN, or ═NR′; and wherein said aryl or heteroaryl is optionallysubstituted with one to four substituents independently selected fromhalo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂,—N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂,—S(O)R′, or —N(R′)S(O)₂R′;

[0064] each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N (R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N (R″)CO₂R″,—CO₂R″, —C(O)R″, C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N (R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N (R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and

[0065] each R″ is independently selected from H or alkyl.

[0066] It will be apparent to one skilled in the art that certaincompounds of this invention may exist in tautomeric forms, all suchtautomeric forms of the compounds being within the scope of theinvention. For example, a tautomeric form of compounds of formula I isshown in formula II wherein Y is N.

[0067] Unless otherwise stated, structures depicted herein are alsomeant to include all stereochemical forms of the structure; i.e., the Rand S configurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

[0068] Certain preferred compounds of the present invention are thosehaving the formula I:

[0069] R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R;

[0070] R₂ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl; orheteroaryl; wherein said alkyl, carbocyclyl, or heterocyclyl isoptionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR, ═NN(R)COR, ═NNRCO₂R,═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, or —NRS(O)₂R;

[0071] X is O, S or —NH;

[0072] Y is CH;

[0073] each R is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR″C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O,═S, ═NN(R′)₂, ═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or═NR′; and wherein said aryl or heteroaryl is optionally substituted withone to four substituents independently selected from halo, —R′, —OR′,—SR′, —NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′,—CO₂R′, —C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, or—N(R′)S(O)₂R′;

[0074] each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″,—CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N (R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and

[0075] each R″ is independently selected from H or alkyl; with theproviso that when X is NH and R₁ is an unsubstituted phenyl, then R₂ isnot

[0076] In a preferred embodiment, X is —NH or O and all other variablesare as defined immediately above.

[0077] Other preferred compounds of the instant invention are thosehaving the formula I:

[0078] R₁ is selected from carbocyclyl; heterocyclyl; aryl; heteroaryl;or —CN; wherein said carbocyclyl or heterocyclyl is optionallysubstituted with one to four substituents independently selected fromhalo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R,—CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O,═S, ═NN(R)₂, ═N—OR, ═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R, —OR, —SR, —NO₂,—CN, —N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R;

[0079] R₂ is selected from aryl; heteroaryl; carbocyclyl; orheterocyclyl; wherein said carbocyclyl or heterocyclyl is optionallysubstituted with one to four substituents independently selected fromhalo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R,—CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O,═S, ═NN(R)₂, ═N—OR, ═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R, —OR, —SR, —NO₂,—CN, —N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R;

[0080] X is O, S or —NH;

[0081] Y is N;

[0082] each R is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′,═O, —S, ═NN(R′)₂, ═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′,═N—CN, or ═NR′; and wherein said aryl or heteroaryl is optionallysubstituted with one to four substituents independently selected fromhalo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂,—N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂,—S(O)R′, or —N(R′)S(O)₂R′;

[0083] each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″,—CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N(R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and

[0084] each R″ is independently selected from H or alkyl; with theproviso that:

[0085] i) when X is —NH and R₂ is an unsubstituted phenyl, then R₁ isnot an unsubstituted phenyl;

[0086] ii) when X is O and R₁ is heterocyclyl, aryl or heteroaryl, thenR₂ is not heteroaryl or heterocyclyl; and

[0087] iii) R₁ excludes the following groups: unsubstituted 3-pyridyl,unsubstituted naphthyl,

[0088] In a preferred embodiment, X is —NH or O and all other variablesare as defined immediately above.

[0089] In another preferred embodiment, R₂ is an optionally substitutedphenyl. In certain embodiments, R₁ is substituted aryl or substitutedheteroaryl and R₂ is an optionally substituted phenyl. In otherembodiments, R₁ is an substituted phenyl or an substituted pyridyl andR₂ is an optionally substituted phenyl. In further preferredembodiments, R₁ is phenyl or pyridyl wherein said phenyl or pyridyl issubstituted with —R₈, —O-(alkyl optionally substituted with —CO₂R₃, —OR₃or —N(R₃)₂), —O-aralkyl, —O-carbocyclyl, —CO₂R₃, —SO₂R₃, —SO₂N (R₃)₂,—CF₃, halo, —CN, or heterocyclyl optionally substituted with ═O oralkyl; R₂ is phenyl optionally substituted with —NO₂, —N(R₃)₂, —OR₃,—O-aryl, —O-aralkyl, —O-heterocyclylalkyl, —O-(alkyl optionallysubstituted with R⁺ or R₁₀), —O—CF₃, —CF₃, halo, —CN, —C(O)NH₂,—C(O)N(R₁₀)₂, —CO₂R₃, —S(O)₂NH₂, —S(O)₂N(R₁₀)₂, —S(O)₂N (R₄)₂,—S(O)₂R₁₀, R₃, R₄, —NR₃C(O)R₁₀, R₁₀, R⁺, —C(O)-aryl, or aryl optionallysubstituted with —NR″C(O)R″, —N(R″)₂, —CF₃, halo, —CN, —C(O)R″, —OR″,—O-aryl, or R₁₀; each R₃ is independently selected from H or alkyl; eachR₄ is independently heteroaryl or heterocyclyl, wherein heterocyclyl isoptionally substituted with ═O, —CO₂R″ or alkyl; each R₁₀ isindependently alkyl optionally subsutituted with one or foursubstituents independently selected from the group consisting of —OR″,—CO₂R″, SO₂N(R″)₂, —N(R″)₂, NR″C(O)R″ and CN; and R⁺ is —N(R′)₂ whereinR′ is alkyl optionally substituted with —OR′.

[0090] In another preferred embodiment, R₁ is selected from H, alkyl,heterocyclyl, aryl, or heteroaryl, wherein said alkyl or heterocyclyl isoptionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR, ═NN(R)COR, ═NNRCO₂R,═NNRSO₂R, ═N—CN, or ═NR, and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, or —NRS(O)₂R; R₂ is alkyl, carbocyclyl, heterocyclyl, aryl orheteroaryl, wherein said alkyl, carbocyclyl, or heterocyclyl isoptionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR, ═NN(R)COR, ═NNRCO₂R,═NNRSO₂R, ═N—CN, or ═NR, and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, or —NRS(O)₂R; X is —NH or O and Y is N or CH.

[0091] In another preferred embodiment, R₁ is H, alkyl, heterocyclyl,aryl, or heteroaryl, wherein said alkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one to four substituentsindependently selected from —OR, —CO₂R, —SO₂N(R)₂, —SO₂R, R₈, —CF₃,halo, —CN, or heterocyclyl optionally substituted with ═O or alkyl; R₂is alkyl, carbocyclyl, heterocyclyl, heterocyclyl substituted by ═O,aryl or heteroaryl, wherein said alkyl, carbocyclyl, heterocyclyl, arylor heteroaryl is optionally substituted with one to four substituentsindependently selected from —NO₂, —N(R)₂, —OR, —CF₃, halo, —CN, —CO₂R,—C(O)R, —C(O)N(R)₂, —N(R)C(O)R, —S(O)₂N(R)₂, —SO₂R, R⁺, or R; R is H,CF₃, alkyl optionally substituted with R₇, aralkyl, heteroaryloptionally substituted with R₉, heterocyclyl optionally substituted withR₇, heterocyclylalkyl, carbocyclyl, or aryl optionally substituted with—NR″C(O)R″, —N(R″)₂, —NR″C(O)N(R″)₂, —NR″S(O)₂R″, —NO₂, —CF₃, halo, —CN,—CO₂R″, —C(O)N(R″)₂, —C(O)R″, —SR″, —S(O)R″, —S(O)₂R″, —S(O)₂N(R″)₂,—OR″, —O-aryl, or alkyl optionally substituted with —OR″ or —CO₂R″; R⁺is —N(R′)₂ wherein R′ is alkyl optionally substituted with —OR″; R₇ isindependently selected from the group consisting of ═O, OR″, R⁺,—N(R″)₂, R₈, —CO₂R″, —SO₂N(R″)₂, —NR″C(O)R″, —CN and R″; R₈ is alkylsubstituted with —OR″; R₉ is heterocyclyl or alkyl wherein alkyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of —OR″ and —CO₂R″; X is —NH or O andY is N or CH.

[0092] In yet another preferred embodiment, each R₁ and R₂ isindependently heterocyclyl, aryl or heteroaryl, wherein saidheterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N (R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN (R)₂, ═N—OR, ═NN (R)COR,═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR, and wherein said aryl or heteroarylis optionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, or —NRS(O)₂R; X is —NH or 0 and Y is N or CH.

[0093] In another preferred embodiment, R₁ is H, alkyl, heterocyclyl,heteroaryl, or aryl, wherein each member of R₁ except H is optionallysubstituted with one to four substituents independently selected —OH,—R₈, —O-(alkyl optionally substituted with —CO₂R₃, —OR₃ or —N(R₃)₂),—O-aralkyl, —O-carbocyclyl, —CO₂R₃, —SO₂R₃, —SO₂N(R₃)₂, —CF₃, halo, —CN,or heterocyclyl optionally substituted with ═O or alkyl; R₂ is alkyl,carbocyclyl, heterocyclyl, heterocyclyl substituted with ═O, aryl orheteroaryl, wherein each member of R₂ is optionally substituted with oneto four substituents independently selected from —NO₂, —N(R₃)₂, —OR₃,—O-aryl, —O-aralkyl, —O-heterocyclylalkyl, —O-(alkyl optionallysubstituted with R⁺ or R₁₀), —O—CF₃, —CF₃, halo, —CN, —C(O)NH₂,—C(O)N(R₁₀)₂, —CO₂R₃, —S(O)₂NH₂, —S(O)₂N(R₁₀)₂, —S(O)₂N(R₄)₂, —S(O)₂R₁₀,R₃, R₄, —NR₃C(O)R₁₀, R₁₀, R⁺, —C(O)-aryl, or aryl optionally substitutedwith —NR″C(O)R″, —N(R″)₂, —NO₂, —CF₃, halo, —CN, —C(O)R″, —OR″, —O-aryl,or R₁₀; each R₃ is independently selected from H or alkyl; each R₄ isindependently heteroaryl or heterocyclyl, wherein heterocyclyl isoptionally substituted with ═O, —CO₂R″ or alkyl; each R₁₀ isindependently alkyl optionally subsutituted with one or foursubstituents independently selected from the group consisting of —OR″,—CO₂R″, SO₂N(R″)₂, —N(R″)₂, NR″C(O)R″ and CN; X is —NH or O and Y is Nor CH.

[0094] In yet another preferred embodiment, R₁ is H, methyl, i-propyl,benzodioxolyl, dihydrobenzodioxinyl, thienyl, pyridyl, phenyl,dihydrobenzodioxepinyl, pyrrolyl, or benzofuranyl, whereinbenzodioxolyl, dihydrobenzodioxinyl, thienyl, pyridyl, phenyl,dihydrobenzodioxepinyl, pyrrolyl, or benzofuranyl is optionallysubstituted with one to four substituents independently selected from—OH, morpholinyl, dimethylazetidinone, —O-cyclopropyl, —O-cyclopentyl,R₈, —O-(alkyl optionally substituted with —CO₂R₃, —OR₃ or —N(R₃)₂),—O-aralkyl, —CO₂R₃, —SO₂R₃, —SO₂N(R₃)₂, —F, —CF₃, or —CN; R₂ is phenyl,dihydrobenzodioxinyl, tetrahydropyrimidinone, triazolyl, thiazolyl,hexahydropyridopyrazinone, dihydrobenzothiophene dioxide,dihydrobenzodioxepinyl, tetrahydroquinolinyl, dihydroindolyl, thienyl,pyridyl, benzyl, benzodioxolyl, carbazolyl, fluorenonyl, pyrazolyl, orcyclohexyl, wherein said phenyl, dihydrobenzodioxinyl,tetrahydropyrimidinone, triazolyl, thiazolyl, hexahydropyridopyrazinone,dihydrobenzothiophene dioxide, dihydrobenzodioxepinyl,tetrahydroquinolinyl, dihydroindolyl, thienyl, pyridyl, benzyl,benzodioxolyl, carbazolyl, fluorenonyl, pyrazolyl, or cyclohexyl isoptionally substituted with one to four substituents independentlyselected from —NO₂, pyrazolidinone, dioxolanyl, —N(R₃)₂, —O(R₃)₂,—O—CF₃, —CF₃, —F, —Cl, —Br, —CN, —C(O)N(R₁₀)₂, R₁₀, R₈, morpholinyl,—SO₂N(R₃)₂, —SO₂-morpholinyl, —SO₂-piperazinedione, —SO₂N(R₃)₂, —SO₂R₈,—CO₂R₃, —CO₂R₈, —NR₃C(O)R₃, —O-phenyl, —O-Bn, —O-pyridyl, —C(O)-phenyl,pyridyl, thienyl, benzodioxolyl, furanyl, tetrahydrofuranyl optionallysubstituted with R₈, pyrrolidinone optionally substituted with —CO₂R″,imidazolyl, —N-methylpiperazinyl, R⁺, —O-alkyl wherein alkyl issubstituted with R₁₀ or morpholinyl, or phenyl optionally substitutedwith one to four substituents independently selected from —N(R″)₂, —OR″,alkyl optionally substituted with —OR″ or —CO₂R″, benzodioxolyl,pyrrolyl, piperazinedione, —C(O)R″, —NR″CO(R″), or —OPh; X is —NH or Oand Y is N or CH.

[0095] In another preferred embodiment of the invention, X is —NH.

[0096] Another preferred embodiment of the invention is shown in formulaIII:

[0097] wherein R₅ is H, —R₈, —O-(alkyl optionally substituted with—CO₂R₃, —OR₃ or —N(R₃)₂), —O-aralkyl, —O-carbocyclyl, —CO₂R₃, —SO₂R₃,—SO₂N(R₃)₂, —CF₃, halo, —CN, or heterocyclyl optionally substituted with═O or alkyl; R₆ is —NO₂, —N(R₃)₂, —OR₃, —O-aryl, —O-aralkyl,—O-heterocyclylalkyl, —O-(alkyl optionally substituted with R⁺ or R₁₀),—O—CF₃, —CF₃, halo, —CN, —C(O)NH₂, —C(O)N(R₁₀)₂, —CO₂R₃, —S(O)₂NH₂,—S(O)₂N(R₁₀)₂, —S(O)₂N(R₄)₂, —S(O)₂R₁₀, R₃, R₄, —NR₃C(O)R₁₀, R₁₀, R⁺,—C(O)-aryl, or aryl optionally substituted with —NR″C(O)R″, —N(R″)₂,—CF₃, halo, —CN, —C(O)R″, —OR″, —O-aryl, or R₁₀; each R₃ isindependently selected from H or alkyl; each R₄ is independentlyheteroaryl or heterocyclyl, wherein heterocyclyl is optionallysubstituted with ═O, —CO₂R″ or alkyl; each R₁₀ is independently alkyloptionally subsutituted with one or four substituents selected from thegroup consisting of —OR″, —CO₂R″, SO₂N(R″)₂, —N(R″)₂, NR″C(O)R″ and CN;and and n is 1, 2, or 3. More preferably, R₅ is H, CF₃, F, morpholinyl,tetrahydropyrimidinone, —O—CH₂CH₂N(CH₃)₂, CN or —OCH₃ and R₆ is —NO₂,halo, —OCH₃, —O-cyclopropyl, —O-cyclopentyl, CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,pyridyl, pyrrolidinone, N-methylpiperazinyl, thienyl, benzodioxolyl,morpholinyl, furanyl, imidazolyl, tetrahydrofuranyl, dioxolanyl,—NHCOMe, —CF₃, —CONH₂, —CN, —OPh, —OBn, —COPh, —SO₂NH₂, —CO₂Me,—N(Et)(CH₂CH₂OH), —O—(CH₂)₃—NMe₂, —O—(CH₂)₃-morpholinyl, or phenyloptionally substitited by —O-phenyl, —C(O)Me, F, —NHCOMe, —NH₂, —NMe₂,—OMe, —OEt, benzodioxolyl, pyrrolyl, piperazinedione, —CH₂CH₂CO₂H, or—CH₂OH.

[0098] Representative examples of compounds of the present invention areshown below in Table 1 (the downward bond on the right side in the R₁column and the downward bond on the left side in the R₂ column indicatethe point of attachment to the remainder of the molecule). TABLE 1

Compound No. Y R₁ R₂ 1 N H

2 N H

3 N

4 N

5 N H

6 N

7 N

8 N

9 N

10 N

11 N H

12 N

13 N

14 N

15 N

16 N

17 N

18 N

19 N

20 N

21 N

22 N

23 N

24 N

25 N

26 N

27 N

28 N

29 N

30 N

31 N

32 N

33 N

34 N

35 N

36 N

37 N

38 N

39 N

40 N

41 N

42 N

43 N

44 N

45 N

46 N

47 N

48 N

49 N

50 N

51 N

52 N

53 N

54 N

55 N

56 N

57 N

58 N

59 N

60 N

61 N

62 N

63 N

64 N

65 N

66 N

67 N

68 N

69 N

70 N

71 N

72 N

73 N

74 N

75 N

76 N

77 N

78 N

79 N

80 N

81 N

82 N

83 N

84 N

85 N

86 N

87 N

88 N

89 N

90 N

91 CH

92 CH

93 CH

94 CH

95 CH

96 CH

97 CH

98 CH

99 CH

100 CH

101 CH

102 CH

103 CH

104 CH

105 N

106 N

107 N

108 N

109 N

110 N

111 N

112 N

113 N

114 N

115 N

116 N

117 N

118 N

119 N

120 N

121 N

122 N

123 N

124 N

125 N

126 N

127 N

128 N

129 N

130 N

131 N

132 N

133 N

134 N

135 N

136 N

137 N

138 N

139 N

140 N

141 N

142 N

143 N

144 N

145 N

146 N

147 N

148 N

149 N

150 N

151 N

152 N

153 N

154 N

155 N

156 N

157 N

158 N

159 N

160 N

161 N

162 N

163 N

164 N

165 N

166 N

167 N

168 N

169 N

170 N

171 N

172 N

173 N

174 N

175 N

176 N

177 N

178 N

179 N

180 N

181 N

182 N

183 N

184 N

185 N

186 N

187 N

188 N

189 N

190 N

191 N

192 N

193 N

194 N

195 N

196 N

197 N

198 N

199 N

200 N

201 N

202 N

203 N

204 N

205 N

206 N

207 N

208 N

209 N

210 N

211 N

212 N

213 N

214 N

215 N

216 N

217 N

218 N

219 N

220 N

221 N

222 N

223 N

224 CH

225 N

226 N

227 CH

228 N

229 N

230 N

231 N

232 N

233 N

234 N

235 N

236 N

237 N

238 N

239 N

240 N

241 N

242 N

243 N

244 N

245 N

246 N

247 N

248 N

249 N

250 N

251 N

252 N

253 N

254 N

255 N

256 N

257 N

258 N

259 N

260 N

261 N

262 N

263 N

264 N

265 N

266 N

267 N

268 N

269 N

270 N

271 N

272 N

273 N

274 N

275 N

276 N

277 N

278 N

279 N

280 N

281 N

282 N

283 N

284 N

285 N

286 N

287 N

288 N

289 N

290 N

[0099] The exemplary compounds of this invention generally may beprepared from known starting materials, following methods known to thoseskilled in the art for analogous compounds, as illustrated by generalSchemes I-III.

[0100] Scheme I shows a general approach for making the presentcompounds. The starting material β-keto esters were either commerciallyavailable or readily synthesized following methods known in the art, forinstance, those described in Jung, M. E., Lau, P., Mansuri, M. M. andSpeltz, L. M., J. Org. Chem., 50, 1087 15 (1985). Step (i) was carriedout following the method as described in Zauhar, J. and Ladoucheur, B.F., Can. J. Chem., 46, 1079 (1968) and step (ii) was carried outfollowing the method as described in Zollinger, H. Color Chemistry:Synthesis, Properties and Applications of Organic Dyes and Pigments,2^(nd) ed., VCH, pp. 109-180 (1991).

[0101] In certain embodiments of the invention, compounds of formula Ican be prepared from the reagents (R₁COCH₃ and R₂—NH₂) depicted below inTables 2A and 2B. TABLE 2A Exemplary Reagents - R₁COCH₃

[0102] TABLE 2B Exemplary Reagents - R₂—NH₂

[0103]

[0104] Scheme II shows a general synthetic route that is used forpreparing the compounds of formula I where Y is CH and R¹ is aryl(denoted as Ar in Scheme II).

[0105] 5-Aryl-2,4-dihydro-pyrazol-3-one (a) in dry actonitrile was addedC-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (b) and stirred. Thereaction was monitored by HPLC. After 36 hours, the solid (c) wasfiltered and rinsed with dry acetonitrile and dried under nitrogenpressure.

[0106] 4-Dimethylaminomethylene-5-aryl-2,4-dihydro-pyrazol-3-one (c) wascombined with amine (d) in acetonitrile and heated to reflux for 8˜16hours with/without catalytic amount of acetic acid. The reaction wasmonitored by HPLC. After the reaction was complete, the mixture was keptat room temperature to form solid. The product (e) was filtered andwashed with acetonitrile/methanol. The details of the conditions usedfor producing these compounds are set forth in the Examples.

[0107] Scheme III above shows a general synthetic route that is used forpreparing the compounds of formula I where X is NH, Y is N, R¹ is aryl(denoted as Ar in Scheme III) and R² is an Ar′ substituted anisole (Ar′denotes an aryl) by Suzuki coupling which was described by O'Neill etal., J. Med. Chem., 40, pp. 437-448 (1997).

[0108] Step i was carried out following the method as described inZollinger, H. Color Chemistry: Synthesis, Properties and Applications ofOrganic Dyes and Pigments, 2^(nd) ed., VCH, pp. 109-180 (1991). Afterthe aryl bromide (h, 50 mg, 0.11 mmol) was partially dissolved intoluene (1 mL), ethanol (0.2 mL) and several drops of water, sodiumcarbonate (24 mg, 0.22 mmol), an aromatic boronic acid (i, 0.12 mmol)and tetrakis(triphenylphosphine) palladium (12 mg) were subsequentlyadded. The reaction tube was sealed and heated to 100° C. for 5-12hours. After cooling, several mL of brine were added and the mixture wasextracted with methylene chloride. The solvent was dried and removed.The residue was then purified by silica gel chromatography or reversephase HPLC to give the product (j). Exemplary aromatic boronic acids (i)are depicted below in Table 3. TABLE 3 Exemplary Aromatic Boronic Acidsi

[0109] One having ordinary skill in the art may synthesize othercompounds of this invention following the teachings of the specificationusing reagents that are readily synthesized or commercially available.

[0110] Another object of the instant invention is to provide methods forinhibiting GSK-3 activity comprising the step of administering compoundshaving formula (I).

[0111] The activity of the compounds as protein kinase inhibitors,particularly as GSK-3 inhibitors, may be assayed in vitro, in vivo or ina cell line. In vitro assays include assays that determine inhibition ofeither the phosphorylation activity or ATPase activity of activatedGSK-3. Alternate in vitro assays quantitate the ability of the inhibitorto bind to GSK-3. Inhibitor binding may be measured by radiolabellingthe inhibitor prior to binding, isolating the inhibitor/GSK-3 complexand determining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with GSK-3 bound to known radioligands.

[0112] The compounds of the present invention may also be effective asAurora protein kinase inhibitors or cyclin-dependent kinases,particularly as Aurora-2 or CDK-2 inhibitors. Accordingly, thesecompounds are useful for treating or preventing Aurora-2- orCDK-2-mediated conditions and in methods for inhibiting Aurora-2 orCDK-2 activity.

[0113] The activity of the compounds as Aurora-2 or CDK-2 inhibitors maybe assayed in vitro, in vivo or in a cell line using similar proceduresas described above for GSK-3.

[0114] According to one embodiment of the invention, compounds offormula I or salts thereof may be formulated into compositions. In apreferred embodiment, the composition is a pharmaceutical composition.In one embodiment, the composition comprises an amount of the proteinkinase inhibitor effective to inhibit a protein kinase, particularlyGSK-3, in a biological sample or in a patient. In another embodiment,compounds of this invention and pharmaceutical compositions thereof,which comprise an amount of the protein kinase inhibitor effective totreat or prevent a GSK-3-mediated condition and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle, may be formulated foradministration to a patient.

[0115] Another aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0116] Another aspect of the invention relates to inhibiting GSK-3activity in a biological sample, which method comprises contacting thebiological sample with the GSK-3 inhibitor of formula I.

[0117] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0118] Another aspect of this invention relates to a method for treatingor preventing an Aurora-2-mediated disease state with an Aurora-2inhibitor, which method comprises administering to a patient in need ofsuch a treatment a therapeutically effective amount of a compound offormula I or a pharmaceutical composition thereof.

[0119] Another aspect of the invention relates to inhibiting Aurora-2activity in a biological sample, which method comprises contacting thebiological sample with the Aurora-2 inhibitor of formula I, or acomposition thereof.

[0120] Another aspect of the invention relates to inhibiting CDK-2activity in a biological sample or a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0121] Another aspect of this invention relates to a method for treatingor preventing a CDK-2-mediated disease state with a CDK-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formula Ior a pharmaceutical composition thereof.

[0122] The term “pharmaceutically acceptable carrier, adjuvant, orvehicle” refers to a non-toxic carrier, adjuvant, or vehicle that may beadministered to a patient, together with a compound of this invention,and which does not destroy the pharmacological activity thereof.

[0123] The term “patient” includes human and veterinary subjects.

[0124] The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

[0125] The term “GSK-3-mediated condition” or “state”, as used herein,means any disease or other deleterious condition or state in whichGSK-3, in particular GSK-3, is known to play a role. Such diseases orconditions include, without limitation, diabetes, Alzheimer's disease,Huntington's Disease, Parkinson's Disease, AIDS-associated dementia,amyotrophic lateral sclerosis (AML), multiple sclerosis (MS),schizophrenia, cardiomycete hypertrophy, reperfusion/ischemia, andbaldness.

[0126] The term “Aurora-2-mediated condition” or “state”, as usedherein, means any disease or other deleterious condition in which Aurorais known to play a role. Such conditions include, without limitation,cancer. The term “cancer” includes, but is not limited to the followingcancers: colon and ovarian.

[0127] The term “CDK-2-mediated condition” or “state”, as used herein,means any disease or other deleterious condition in which CDK-2 is knownto play a role. Such conditions include, without limitation, cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

[0128] The amount effective to inhibit protein kinase, for example,GSK-3, Aurora-2 and CDK-2, is one that inhibits the kinase activity atleast 50%, more preferably at least 60% or 70%, even more preferably atleast 80% or 90%, and most preferably at least 95%, where compared tothe activity of the enzyme in the absence of an inhibitor. Any methodmay be used to determine inhibition. See, e.g., Examples 1-3.

[0129] Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

[0130] The compositions of the present invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

[0131] Sterile injectable forms of the compositions of this inventionmay be aqueous or oleaginous suspension. These suspensions may beformulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents which arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms mayalso be used for the purposes of formulation.

[0132] The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,favoring or coloring agents may also be added.

[0133] Alternatively, the pharmaceutical compositions of this inventionmay be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient which is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

[0134] The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

[0135] Topical application for the lower intestinal tract can beeffected in a rectal suppository formulation (see above) or in asuitable enema formulation. Topically-transdermal patches may also beused.

[0136] For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

[0137] For ophthalmic use, the pharmaceutical compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or, preferably, as solutions in isotonic, pH adjusted sterilesaline, either with or without a preservative such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticalcompositions may be formulated in an ointment such as petrolatum.

[0138] The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

[0139] In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified diseases or disorders.

[0140] A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

[0141] Pharmaceutically acceptable prodrugs of the compounds of thisinvention include, without limitation, esters, amino acid esters,phosphate esters, metal salts and sulfonate esters.

[0142] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acid saltsinclude acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate,picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

[0143] Salts derived from appropriate bases include alkali metal (e.g.,sodium and potassium), alkaline earth metal (e.g., magnesium), ammoniumand N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions thequaternization of any basic nitrogen-containing groups of the compoundsdisclosed herein. Water or oil-soluble or dispersible products may beobtained by such quaternization.

[0144] The amount of the protein kinase inhibitor that may be combinedwith the carrier materials to produce a single dosage form will varydepending upon the patient treated and the particular mode ofadministration. Preferably, the compositions should be formulated sothat a dosage of between 0.01-100 mg/kg body weight/day of the inhibitorcan be administered to a patient receiving these compositions.

[0145] It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of the inhibitor will also depend upon the particular compound inthe composition.

[0146] Depending upon the particular protein kinase-mediated conditionto be treated or prevented, additional drugs, which are normallyadministered to treat or prevent that condition, may be administeredtogether with the inhibitors of this invention. For example, in thetreatment of diabetes other anti-diabetic agents may be combined withthe GSK-3 inhibitors of this invention to treat diabetes. These agentsinclude, without limitation, insulin, in injectable or inhalation form,glitazones, and sulfonyl ureas.

[0147] Those additional agents may be administered separately from theprotein kinase inhibitor-containing composition, as part of a multipledosage regimen. Alternatively, those agents may be part of a singledosage form, mixed together with the protein kinase inhibitor of thisinvention in a single composition.

[0148] In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLE 1 K_(i) Determination for the Inhibition of GSK-3

[0149] Compounds were screened for their ability to inhibit GSK-3β (AA1-420) activity using a standard coupled enzyme system (Fox et al.(1998) Protein Sci. 7, 2249). Reactions were carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 300 μM NADH,1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were20 μM ATP (Sigma Chemicals, St Louis, Mo.) and 300 μM peptide(HSSPHQS(PO₃H₂)EDEEE, American Peptide, Sunnyvale, Calif.). Reactionswere carried out at 30° C. and 20 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

[0150] An assay stock buffer solution was prepared containing all of thereagents listed above with the exception of ATP and the test compound ofinterest. The assay stock buffer solution (175 μl) was incubated in a 96well plate with 5 μl of the test compound of interest at finalconcentrations spanning 0.002 μM to 30 μM at 30 ° C. for 10 min.Typically, a 12 point titration was conducted by preparing serialdilutions (from 10 mM compound stocks) with DMSO of the test compoundsin daughter plates. The reaction was initiated by the addition of 20 μlof ATP (final concentration 20 μM). Rates of reaction were obtainedusing a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.)over 10 min at 30° C. The K_(i) values were determined from the ratedata as a function of inhibitor concentration.

[0151] The following compounds were shown to have K_(i) values less than0.1 μM for GSK-3: compounds 18-25, 36-37, 43-75, 77-78, 80, 82-83,85-90, 97-98, 105-106, 109, 120-126, 203-208, 213, 217-218, 220, 223,and 225.

[0152] The following compounds were shown to have K_(i) values between0.1 and 1.0 μM for GSK-3: compounds 8, 12, 14-17, 26-27, 33, 38, 40, 76,84, 91-93, 95-96, 111-113, 224, and 227.

[0153] The following compounds were shown to have K_(i) values between1.0 and 20 μM for GSK-3: compounds 1-7, 9-11, 13, 28-32, 34-35, 39,41-42, 79, 81, 103, 212, 215-216, 219, 222, and 226.

EXAMPLE 2 K_(i) Determination for the Inhibition of Aurora-2

[0154] Compounds were screened in the following manner for their abilityto inhibit Aurora-2 using a standard coupled enzyme assay (Fox et al.(1998) Protein Sci. 7, 2249).

[0155] To an assay stock buffer solution containing 0.1M HEPES 7.5, 10mM MgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH,30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and800 μM peptide (LRRASLG, American Peptide, Sunnyvale, Calif.) was addeda DMSO solution of a compound of the present invention to a finalconcentration of 30 μM. The resulting mixture was incubated at 30° C.for 10 min. The reaction was initiated by the addition of 10 μL ofAurora-2 stock solution to give a final concentration of 70 nM in theassay. The rates of reaction were obtained by monitoring absorbance at340 nm over a 5 minute read time at 30° C. using a BioRad Ultramarkplate reader (Hercules, Calif.). The Ki values were determined from therate data as a function of inhibitor concentration.

[0156] The following compounds were shown to have K_(i) values less than0.1 μM for Aurora-2: compounds 22-23, 37, 47, 52, 61, 73, 86, 114-116,118-119, and 223.

[0157] The following compounds were shown to have K_(i) values between0.1 and 1.0 μM for Aurora-2: compounds 43, 46, 58, 60, 62, 70, and 117.

[0158] The following compounds were shown to have K_(i) values between1.0 and 20 μM for Aurora-2: compounds 18-21, 33, 36, 44, 45, 48-51,53-57, 59, 63-69, 71-72, 74-75, 77-78, 80, 82-83, 85, 87-90, 203-208,and 213.

EXAMPLE 3 The Inhibition of CDK-2

[0159] Compounds were screened in the following manner for their abilityto inhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998)Protein Sci 7, 2249).

[0160] To an assay stock buffer solution containing 0.1M HEPES 7.5, 10mM MgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH,30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP,and 100 μM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale,Calif.) was added a DMSO solution of a compound of the present inventionto a final concentration of 30 μM. The resulting mixture was incubatedat 30° C. for 10 min. The reaction was initiated by the addition of 10μL of CDK-2/Cyclin A stock solution to give a final concentration of 25nM in the assay. The rates of reaction were obtained by monitoringabsorbance at 340 nm over a 5-minute read time at 30° C. using a BioRadUltramark plate reader (Hercules, Calif.). The K_(i) values weredetermined from the rate data as a function of inhibitor concentration.

[0161] The CDK-2 inhibitory activity of certain compounds of thisinvention is shown in Table 4. TABLE 4 Inhibitory Activity of CDK-2CDK-2 % inhibition @ % inhibition @ Compound No. 10 μM 2 μM 44 94 87 4695 82

[0162] Compound 98 was shown to have K_(i) values between 0.1 and 1.0 μMfor CDK-2.

[0163] The following compounds were shown to have K_(i) values between1.0 and 20 μM for CDK-2: compounds 91-93, 95-97, 106, 114-119, and120-122.

EXAMPLE 4

[0164] As used hereinafter, the term “R_(t)(min)” refers to the HPLCretention time, in minutes, associated with a particular compound. HPLCanalysis utilized to obtain the reported retention time was performedwith HP1100 HPLC and analysis method was 8 minutes overal run with 0minute, 10% B; 1 minute, 30% B; 5 minutes, 90% B; 6.5 minutes, 90% B;and 6.7 minutes, 10% B. A: 0.01% TFA in water, B: 0.01% TFA inacetonitrile. Analytical column was YMC ODS-AQ, 30×100 mm with 1 mL/minflow rate using diodo ray detector (5 wavelength were monitored at 300,280, 254, 220, and 210 nm) at 25° C.

[0165] Preparation of5-(3,4,5-Trimethoxyphenyl)-2,4-Dihydro-Pyrazol-3-one (k):

[0166] To a stirred solution of3-oxo-3-(3,4,5-trimethoxyphenyl)-propionic acid ethyl ester (2.82 g, 10mmol) in dry acetonitrile (15 mL) was added to anhydrous hydrazine (640mL, 20 mmol) at room temperature. After 1 hour, the mixture was heatedto reflux for 16 hours. The mixture was diluted with acetonitrile (20mL) and the solid was filtered. The solid was washed with acetonitrile(10 mL) and dried under nitrogen to afford 2.2 g of title compound (k).

[0167] Preparation of4-Dimethylaminomethylene-5-(3,4,5-Trimethoxyphenyl)-2,4-Dihydro-Pyrazol-3-one(1):

[0168] 5-(3,4,5-Trimethoxyphenyl)-2,4-dihydro-pyrazol-3-one (k, 2 g) indry actonitrile (10 mL) was addedC-tert-Butoxy-N,N,N′,N′-tetramethyl-methanediamine (3 mL) and stirred at35° C. The reaction was monitored by HPLC. After 36 hours, the solid wasfiltered and rinsed with dry acetonitrile (5 mL) and dried undernitrogen pressure to yield the title compound (1).

[0169] The same method was used for the preparation of4-dimethylaminomethylene-5-(3,4-dimethoxyphenyl)-2,4-dihydro-pyrazol-3-one.

[0170] Compounds 91-104 were prepared by using the synthetic routes asoutlined in Scheme II and analogous methods as described above.

[0171] Compound 92:4-[(3-Benzyloxy-phenylamino)-methylene]-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0172] HPLC (R_(t)): 4.767 minutes; MS: 429.17, [M+H]: 430.2; ¹H NMR(500 MHz, DMSO-d₆): 8.48 (brs, 1H), 7.24-7.47 (m, 9H), 7.03 (d, J=8.4Hz, 2H), 6.85 (dd, J=8.2 and 2.1 Hz, 1H), 5.15 (s, 2H), 3.82 (s, 3H) and3.81 (s, 3H).

[0173] Compound 94:4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-methylene]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0174] HPLC (R_(t)): 3.776 minutes; MS: 411.14, [M+H]: 412.2, [M−H]:410.5; ¹H NMR(500 MHz, DMSO-d₆) 11.9 (brs, 1H), 11.50 (s, 1H), 8.41 (s,1H), 7.15 (d, J=2.5 Hz, 1H), 6.93 (m, 3H), 6.88 (d, J=8.6Hz, 1H), 4.25(m, 4H), 3.85 (s, 6H, 2×CH₃) and 3.70 (s, 3H, CH₃).

[0175] Compound 95:3-{[3-(3,4-Dimethoxy-phenyl)-5-oxo-1,5-dihydro-pyrazol-4-ylidenemethyl]-amino}-benzenesulfonamide

[0176] HPLC (R_(t)): 2.67 and 3. 07 minutes; MS: 402.10, [M+H]: 403.0,[M−H]: 401.0; ¹H NMR (500 MHz, DMSO-d₆) 8.50 (s, 1H), 7.84 (s, 1H), 7.78(m, 1H), 7.61 (d, J=4.6 Hz, 2H), 7.43 (s, 2H), 7.30 (d, J=8.3 Hz, 1H),7.28 (s, 1H), 7.04 (d, J=8.3 Hz, 1H), 3.83 (s, 3H) and 3.82 (s, 3H).

[0177] Compound 99:4-Phenylaminomethylene-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0178] HPLC (R_(t)): 5.75 minutes; m/e: 353, MS (ES+): 354.3; ¹H NMR(500 MHz, CDCl₃): 11.7 (bs, 1H), 9.0 (s, 1H), 7.5 (m, 2H), 7.3 (m, 4H),6.8 (s, 2H), 3.95 (s, 6H) and 3.9 (s, 3H).

[0179] Compound 100:4-Cyclohexylaminomethylene-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0180] HPLC (R_(t)): 5.69 minutes; m/e: 359.3, MS (ES+): 360.3; ¹H NMR(500 MHz, CDCl₃): 10.0 (bs, 1H), 9.8 (s, 1H), 7.6 (d, J=10 Hz, 1H), 6.7(s, 1H), 4.85 (s, 6H), 4.80 (s, 3H), 3.2 (bs, 1H) and 2.0−1.0 (m, 10H).

EXAMPLE 5

[0181] Compounds 105-110 were prepared by following the synthetic routeas outlined in Scheme III.

[0182] Compound 105:4-[(3′-Amino-6-methoxy-biphenyl-3-yl)-hydrazono]-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0183] HPLC (R_(t)): 5.11 minutes; m/e: 445.18, MS (ES+): 446.2.

[0184] Compound 106:5-(3,4-Dimethoxy-phenyl)-4-[(4-methoxy-3-pyridin-3-yl-phenyl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0185] HPLC (R_(t)): 4.95 minutes; m/e: 431.16, MS (ES+): 432.1.

[0186] Compound 107:5-(3,4-Dimethoxy-phenyl)-4-[(4-methoxy-3-pyridin-4-yl-phenyl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0187] HPLC (R_(t)): 4.773 minutes; m/e: 431.16, MS (ES+): 432.1.

[0188] Compound 108:5-(3,4-Dimethoxy-phenyl)-4-[(3′-hydroxymethyl-6-methoxy-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0189] HPLC (R_(t)): 6.563 minutes; m/e: 460.18, MS (ES+): 461.2.

[0190] Compound 109:5-(3,4-Dimethoxy-phenyl)-4-[(6,3′,4′,5′-tetramethoxy-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0191] HPLC (R_(t)): 7.350 minutes; m/e: 520.2, MS (ES+): 521.2.

[0192] Compound 110:5-(3,4-Dimethoxy-phenyl)-4-[(4′-dimethylamino-6-methoxy-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0193] HPLC (R_(t)): 5.452 minutes; m/e: 473.21, MS (ES+): 474.1.

EXAMPLE 6

[0194] Compounds 111-116 were prepared by following the synthetic methodas outlined in Scheme I.

[0195] Compound 111:4-[(2,5-Diethoxy-4-morpholin-4-yl-phenyl)-hydrazono]-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0196] HPLC (R_(t)): 6.453 minutes; m/e: 497.22, MS (ES+): 498.3.

[0197] Compound 112:5-(3,4-Dimethoxy-phenyl)-4-[(2,4,6-trimethoxy-phenyl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0198] HPLC (R_(t)): 6.584 minutes; m/e: 414.15, MS (ES+): 415.2.

[0199] Compound 113:5-(4-Hydroxy-3-methoxy-phenyl)-4-[(2-methoxy-4-morpholin-4-yl-phenyl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0200] HPLC (R_(t)): 5.420 minutes; m/e: 425.16, MS (ES+): 426.3.

[0201] Compound 114:5-(3,4-Diethoxy-phenyl)-4-[(4-diethylamino-phenyl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0202] HPLC (R_(t)): 5.340 minutes; m/e: 423.23, MS (ES+): 424.2.

[0203] Compound 115:5-(3,4-Diethoxy-phenyl)-4-({4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl}-hydrazono)-2,4-dihydro-pyrazol-3-one

[0204] HPLC (R_(t)): 4.942 minutes; m/e: 439.99, MS (ES+): 440.2.

[0205] Compound 116:5-(3,4-Diethoxy-phenyl)-4-[(4-morpholin-4-yl-phenyl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0206] HPLC (R_(t)): 6. 771 minutes; m/e: 437.21, MS (ES+): 438.1.

EXAMPLE 7

[0207]

[0208] 1-(4-Benzyloxy-3-methoxy-phenyl)-ethanone (m) was prepared andcharacterized as described in J. Org. Chem., 57, p. 7248 (1992).

[0209] 5-(4-Benzyloxy-3-methoxy-phenyl)-2,4-dihydro-pyrazol-3-one (o)was prepared from 1-(4-benzyloxy-3-methoxy-phenyl)-ethanone (m) usingthe method as described in Scheme I.3-(4-Benzyloxy-3-methoxy-phenyl)-3-oxo-propionic acid methyl ester (n):m/e: 314.12, MS (ES+): 315.0.5-(4-Benzyloxy-3-methoxy-phenyl)-2,4-dihydro-pyrazol-3-one (o): m/e:296.12, MS (ES+): 297.0; ¹H NMR (500 MHz, DMSO-d₆): 12.0 (bs, 1H), 9.8(bs, 1H), 7.5−7.0 (m, 8H), 5.9 (s, 1H), 5.1 (s, 2H) and 3.8 (s, 3H).

[0210] Compounds 117-119 were prepared from5-(4-benzyloxy-3-methoxy-phenyl)-2,4-dihydro-pyrazol-3-one (o) using themethod as described in Scheme I.

[0211] Compound 117:5-(4-Benzyloxy-3-methoxy-phenyl)-4-[(4-diethylamino-phenyl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0212] HPLC (R_(t)): 5.945 minutes; m/e: 471.23, MS (ES+): 472.1.

[0213] Compound 118:5-(4-Benzyloxy-3-methoxy-phenyl)-4-({4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl}-hydrazono)-2,4-dihydro-pyrazol-3-one

[0214] HPLC (R_(t)): 5.584 minutes; m/e: 48 7.2, MS (ES+): 488.1.

[0215] Compound 119:5-(4-Benzyloxy-3-methoxy-phenyl)-4-[(4-morpholin-4-yl-phenyl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0216] HPLC (R_(t)): 5.773 min; m/e: 485.221, MS (ES+): 486.1.

EXAMPLE 8

[0217]

[0218] 2-(3-Bromo-propoxy)-biphenyl (p) was prepared by treatingbiphenyl-2-ol (6.2 g, 36 mmol) and 3-bomopropanol (5 g, 36 mmol) withDEAD (6.3 g, 36 mmol) and triphenyl phosphine (9.5 g, 36 mmol) in 100 mLTHF at room temperature overnight. The solvent was then evaporated. Thecrude product was purified by silica gel chromatography (eluent: 5%ethylacetate, 50% DCM, 45% hexane) to afford p in 50% yield: ¹H NMR (500MHz, CDCl₃): 7.6−6.9 (m, 9H), 4.1 (m, 2H), 3.5 (m, 2H) and 2.2 (m, 2H).

[0219] The bromide p (6 g, 26 mmol) from the previous step was nitratedin 10 ml acetic acid and 5 mL nitric acid at 0° C. After 2 hours, thereaction mixture was poured into 100 mL water and the product mixturewas filtered and washed with water. The crude product was purified bysilica gel chromatography (eluent: DCM) affording 3 g2-(3-bromo-propoxy)-5-nitro-biphenyl (q) in 45% yield: ¹H NMR (500 MHz,CDCl₃): 8.2 (m, 2H), 7.3 (m, 5H), 6.9 (m, 1H), 4.2 (m, 2H), 3.3 (m, 2H)and 2.2 (2H).

[0220] 2-(3-Bromo-propoxy)-5-nitro-biphenyl (q, 530 mg, 1.57 mmol) wasrefluxed with stannous chloride hydrate (1.1 g, 4.8 mmol) in 5 mLethanol and 3 mL concentrated HCl. After 1.5 hours, the solvent wasevaporated and the mixture was basified with 2N NaOH. The mixture wasthen extracted with DCM, dried and evaporated, affording 250 mg6-(3-bromo-propoxy)-biphenyl-3-ylamine (r) in 50% yield: ¹H NMR (500MHz, CDCl₃): 7.3 (m, 5H), 6.7 (m, 3H), 4.2 (bs, 2H), 3.9 (m, 2H), 3.5(m, 2H) and 2.1 (2H).

[0221] 6-(3-Bromo-propoxy)-biphenyl-3-ylamine (r, 250 mg, 0.82 mmol) wasdiazotized with sodium nitrite (67 mg, 0.98 mmol) in 1:1 water/ethanoland 0.5 mL concentrated HCl at 0° C. After approximately 1 hour, thediazonium solution was added dropwise to a suspension of5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one (200 mg, 0.9 mmol)and sodium acetate (1.1 g) in 10 mL 1:1 water/ethanol. The orange solidwhich precipitated was filtered and washed with water and dried. Thecrude product was purified by silica gel chromatography (eluent: 5%methanol/DCM) to afford 120 mg of4-{[6-(3-bromo-propoxy)-biphenyl-3-yl-hydrazono}-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one(s): HPLC (R_(t)) 5.02 min; m/e 536.1, MS (ES+): 538.9; ¹H NMR (500 MHz,CDCl₃): 13.9 (bs, 1H), 9.0 (bs, 1H), 7.7−6.9 (m, 11H), 4.1 (m, 2H), 3.9(s, 3H), 3.7 (s, 3H), 3.5 (m, 2H), 3.3 (m, 2H), 2.2 (m, 2H) and 2.1 (m,2H).

[0222]5-(3,4-Dimethoxy-phenyl)-4-{[6-(3-dimethylamino-propoxy)-biphenyl-3-yl]-hydrazono}-2,4-dihydro-pyrazol-3-one(compound 121) was prepared by dissolving4-{[6-(3-bromo-propoxy)-biphenyl-3-yl]-hydrazono}-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one(s) in 1 mL of a dimethylamine solution (2 M in THF) and heating to 50°C. for one hour. The solvent was then evaporated and the residue waspurified by silica gel chromatography (eluent: 10% methanol/DCM) toafford 6 mg product (compound 121): HPLC (R_(t)): 5.490 minutes; m/e:501.23, MS (ES+): 502.2.

[0223]4-{[6-(3-Bromo-propoxy)-biphenyl-3-yl]-hydrazono}-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one(s) and Cs₂CO₃ were dissolved in 1 mL (2-hydoxy)ethylmethyl amine andthe resulting soultion was heated to 50° C. for one hour. The solventwas evaporated and the residue was purified by silica gel chromatography(eluent: 10% methanol/DCM) to afford 15 mg5-(3,4-dimethoxy-phenyl)-4-[(6-{3-[(2-hydroxy-ethyl)-methyl-amino]-propoxy}-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one(compound 120): HPLC (R_(t)): 5.525 minutes; m/e: 531.24, MS (ES+):532.2.

EXAMPLE 9

[0224]

[0225] 2-(3-Bromo-propoxy)-biphenyl (1.0 g) was reacted with morpholine(5 mL) at 50° C. for 1 hour to form4-[3-(biphenyl-2-yloxy)-propyl]-morpholine. The excess morpholine wasevaporated and water was added, followed by extraction with ethylacetate. Removal of ethyl acetate afforded 900 mg of4-[3-(biphenyl-2-yloxy)-propyl]-morpholine (t) as an oil which was usedwithout further purification: m/e: 297.17, MS (ES+): 298.2; ¹H NMR (500MHz, CDCl₃): 7.8−7.0 (m, 9H), 4.0 (m, 2H), 3.7 (m, 4H), 2.5 (m, 6H) and1.8 (m, 2H).

[0226] 4-[3-(Biphenyl-2-yloxy)-propyl]-morpholine (t, 500 mg, 1.46 mmol)was dissolved in 3 mL acetic acid and the reaction mixture was cooled inan ice bath. Concentrated nitric acid (3 mL) was added dropwise and themixture was stirred for 15 minutes at 0° C., then at room temperaturefor one hour. The reaction was subsequently poured into 100 mL water andthe pH of the reaction mixture was raised to >7 with 2N NaOH. Theaqueous solution was extracted with ethyl acetate and dried. The solventwas then removed to afford 500 mg4-[3-(5-nitro-biphenyl-2-yloxy)-propyl]-morpholine (u) which was usedwithout further purification: m/e: 342.15, MS (ES+): 343.1; ¹H NMR (500MHz, CDCl₃): 8.2−6.8 (m, 9H), 4.1(m, 2H), 3.7 (m, 4H), 2.5 (m, 6H) and1.8 (m, 2H).

[0227] 4-[3-(5-Nitro-biphenyl-2-yloxy)-propyl]-morpholine (u, 400 mg,1.1 mmol) was dissolved in 10 mL ethanol and hydrogenated at 1 atm.using 10% Pd—C as a catalyst. After the reaction was allowed to stirovernight, the reaction mixture was filtered and the solvent wasevaporated. The residue was purified by silica gel chromatography(eluent: 5% methanol/DCM) to afford 160 mg6-(3-morpholin-4-yl-propoxy)-biphenyl-3-ylamine (v): m/e: 312.18, MS(ES+): 313.2.

[0228] 6-(3-Morpholin-4-yl-propoxy)-biphenyl-3-ylamine (v, 160 mg, 0.51mmol) was diazotized with sodium nitrite (43 mg, 0.62 mmol) in 1:1water/ethanol and 0.5 mL concentrated HCl at 0° C. After approximately 1hour, the diazonium solution was added dropwise to a suspension of5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one (120 mg, 0.51 mmol)and sodium acetate 1.1 g in 10 mL 1:1 water/ethanol. The orange solidwhich precipitated was filtered and washed with water and dried. Theproduct was purified by silica gel chromatography (eluent: 5%methanol:DCM) to afford 150 mg of4-{[6-(3-bromo-propoxy)-biphenyl-3-yl]-hydrazono}-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one(compound 122) in 55% yield: HPLC (R_(t)): 5.552 minutes; m/e: 543.24,MS (ES+): 544.2.

EXAMPLE 10

[0229]

[0230] Compounds x and z were prepared following the method as describedby Buchwald et al., J. Org. Chem. 65, pp. 1158-1174 (2000).

[0231] 2-Bromo-1-methoxy-4-nitro-benzene (810 mg, 4 mmol), morpholine(420 μL,4.8 mmol), cesium carbonate (1.8 g, 5.6 mmol), Pd₂(dba)₃ (75 mg,0.02 mmol) and BINAP (75 mg, 0.03 mmol) were added to 5 mL dry dioxaneunder an argon atmosphere and heated to 80° C. for 6 hours. Aftercooling, the solvent was evaporated and the residue was purified bysilica gel chromatagraphy (eluent: 5% MeOH/DCM) to afford 390 mg4-(2-methoxy-5-nitro-phenyl)-morpholine (w): m/e: 238.09, MS (ES+):239.3 ¹H NMR (500 MHz, CDCl₃): 8.0 (d, J=10 Hz, 1H), 7.8 (s, 1H), 6.9(d, J=10 Hz, 1H), 4.1 (s, 3H), 3.9 (m, 4H) and 3.2(m, 4H).

[0232] 4-(2-Methoxy-5-nitro-phenyl)-morpholine (w, 390 mg) was dissolvedin 10 mL ethanol and reduced under 1 atm H₂ using 10% Pd—C as acatalyst. After 14 hours, the catalyst was filtered off and the solventwas evaporated, affording 240 mg 4-methoxy-3-morpholin-4-yl-phenylamine(x) which was used without further purification: m/e: 208.12, MS (ES+):209.2.

[0233] 4-Methoxy-3-(4-methyl-piperazin-1-yl)-phenylamine (z) wasprepared in a similar fashion.1-(2-Methoxy-5-nitro-phenyl)-4-methyl-piperazine (y): m/e: 251.12, MS(ES+): 252.2. 4-Methoxy-3-(4-methyl-piperazin-1-yl)-phenylamine (z):m/e: 221.1, MS (ES+): 222.2.

[0234] Using the general diazotization and coupling procedures describedearlier, compounds 123-126 were prepared from compound x or z.

[0235] Compound 123:5-(3,4-Dimethoxy-phenyl)-4-[(4-methoxy-3-morpholin-4-yl-phenyl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0236] HPLC (R_(t)): 5.631 minutes; m/e: 439.18, MS (ES+): 440.2.

[0237] Compound 124:4-[(4-Methoxy-3-morpholin-4-yl-phenyl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0238] HPLC (R_(t)): 5.841 minutes; m/e: 469.19, MS (ES+): 470.2.

[0239] Compound 125:5-(3,4-Dimethoxy-phenyl)-4-{[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-hydrazono}-2,4-dihydro-pyrazol-3-one

[0240] HPLC (R_(t)): 4.638 minutes; m/e: 452.21, MS (ES+): 453.3.

[0241] Compound 126:5-(4-Benzyloxy-3-methoxy-phenyl)-4-{[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-hydrazono}-2,4-dihydro-pyrazol-3-one

[0242] HPLC (R_(t)): 5.937 minutes; m/e: 528.24, MS (ES+): 529.3.

EXAMPLE 11

[0243] Compounds 127-132 were prepared by following the method asdescribed in Scheme I.

[0244] Compound 127:4-[(4-Chloro-phenyl)-hydrazono]-5-(6-methoxy-pyridin-3-yl)-2,4-dihydro-pyrazol-3-one

[0245] HPLC (R_(t)): 3.787 minutes; m/e: 328.9, MS (ES+): 329.9.

[0246] Compound 128:4-[(4-Methoxy-phenyl)-hydrazono]-5-(6-methoxy-pyridin-3-yl)-2,4-dihydro-pyrazol-3-one

[0247] HPLC (R_(t)): 3.469 minutes; m/e: 325.02, MS (ES+): 326.02.

[0248] Compound 129:4-[(3-Bromo-phenyl)-hydrazono]-5-(6-methoxy-pyridin-3-yl)-2,4-dihydro-pyrazol-3-one

[0249] HPLC (R_(t)): 3.819 minutes; m/e: 374.99, MS (ES+): 375.99.

[0250] Compound 130:5-(6-Methoxy-pyridin-3-yl)-4-(pyridin-3-yl-hydrazono)-2,4-dihydro-pyrazol-3-one

[0251] HPLC (R_(t)): 2.252 minutes; m/e: 296.11, MS (ES+): 297.11.

[0252] Compound 131:5-(4-Methoxy-phenyl)-4-(pyridin-3-yl-hydrazono)-2,4-dihydro-pyrazol-3-one

[0253] HPLC (R_(t)): 2.695 minutes; m/e: 295.1, MS (ES+): 296.1.

[0254] Compound 132:4-{[4-(4-Methyl-piperazin-1-yl)-phenyl]-hydrazono}-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0255] HPLC (R_(t)): 2.695 minutes (100%); m/e: 452.4, MS (ES+): 453.4.

EXAMPLE 12

[0256] Compounds 133-162 were prepared by following the methods asdescribed herein.

[0257] Compound 133:4-[(6-Methoxy-biphenyl-3-yl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0258] HPLC (R_(t)): 1.562 minutes; m/e: 460.44, MS (ES+): 461.44.

[0259] Compound 134:5-(3,4-Dimethoxy-phenyl)-4-[(6-methoxy-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0260] HPLC (R_(t)): 1.520 minutes; m/e: 430.4, MS (ES+): 431.41.

[0261] Compound 135:5-(3,4-Dimethoxy-phenyl)-4-[(6-methoxy-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0262] HPLC (R_(t)): 1.528 minutes; m/e: 430.29, MS (ES+): 431.29.

[0263] Compound 136:4-[(6-Methoxy-biphenyl-3-yl)-hydrazono]-5-(2,3,4-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0264] HPLC (R_(t)): 1.910 minutes; m/e: 460.28, MS (ES+): 461.28.

[0265] Compound 137:5-(3,4-Dimethoxy-phenyl)-4-[(2-methoxy-biphenyl-4-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0266] HPLC (R_(t)): 1.546 minutes; m/e: 430.5, MS (ES+): 431.50.

[0267] Compound 138:4-[(2-Methoxy-biphenyl-4-yl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0268] HPLC (R_(t)): 1.639 minutes; m/e: 460.34, MS (ES+): 461.34.

[0269] Compound 139:5-(2,4-Dimethoxy-phenyl)-4-[(2-methoxy-biphenyl-4-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0270] HPLC (R_(t)): 1.539 minutes; m/e: 430.48, MS (ES+): 431.48.

[0271] Compound 140:5-(2,5-Dimethoxy-phenyl)-4-[(2-methoxy-biphenyl-4-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0272] HPLC (R_(t)): 1.591 minutes; m/e: 430.33, MS (ES+): 431.33.

[0273] Compound 141:4-[(2-Methoxy-biphenyl-4-yl)-hydrazono]-5-(2,3,4-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0274] HPLC (R_(t)): 1.584 minutes; m/e: 460.33, MS (ES+): 461.33.

[0275] Compound 142:4-[(3′-Amino-6-methyl-biphenyl-3-yl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0276] HPLC (R_(t)): 1.157 minutes; m/e: 459.26, MS (ES+): 460.26.

[0277] Compound 143:4-[(4-Methyl-3-thiophen-3-yl-phenyl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0278] HPLC (R_(t)): 1.657 minutes; m/e: 450.25, MS (ES+): 451.25.

[0279] Compound 144:N-(2′-Methyl-5′-{N′-[5-oxo-3-(3,4,5-trimethoxy-phenyl)-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-biphenyl-3-yl)-acetamide

[0280] HPLC (R_(t)): 1.384 minutes; m/e: 501.28, MS (ES+): 502.28.

[0281] Compound 145:4-[(4′-Ethoxy-6-methyl-biphenyl-3-yl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0282] HPLC (R_(t)): 1.764 minutes; m/e: 488.29, MS (ES+): 489.29.

[0283] Compound 146:4-[(4-Methyl-3-pyridin-3-yl-phenyl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0284] HPLC (R_(t)): 1.077 minutes; m/e: 445.27, MS (ES+): 446.27.

[0285] Compound 147:4-[(3-Benzo[1,3]dioxol-5-yl-4-methyl-phenyl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0286] HPLC (R_(t)): 1.636 minutes; m/e: 488.24, MS (ES+): 489.24.

[0287] Compound 148:4-[(4-Methyl-3-pyridin-4-yl-phenyl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0288] HPLC (R_(t)): 1.071 minutes; m/e: 445.27, MS (ES+): 446.27.

[0289] Compound 149:4-[(4′-Acetyl-6-methyl-biphenyl-3-yl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0290] HPLC (R_(t)): 1.551 minutes; m/e 486.30, MS (ES+): 487.30.

[0291] Compound 150:4-[(3′,4′,5′-Trimethoxy-6-methyl-biphenyl-3-yl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0292] HPLC (R_(t)): 1.538 minutes; m/e: 534.32, MS (ES+): 535.32.

[0293] Compound 151:4-[(3′-Amino-6-methyl-biphenyl-3-yl)-hydrazono]-5-(2,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0294] HPLC (R_(t)): 1.151 minutes; m/e: 429.29, MS (ES+): 430.29.

[0295] Compound 152:5-(2,4-Dimethoxy-phenyl)-4-[(4′-hydroxymethyl-6-methyl-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0296] HPLC (R_(t)): 1.360 minutes; m/e 444.29, MS (ES+): 445.29.

[0297] Compound 153:4-[(3-Benzo[1,3]dioxol-5-yl-4-methyl-phenyl)-hydrazono]-5-(2,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0298] HPLC (R_(t)): 1.587 minutes; m/e: 458.27, MS (ES+): 459.27.

[0299] Compound 154:5-(2,4-Dimethoxy-phenyl)-4-[(3′,4′,5′-trimethoxy-6-methyl-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0300] HPLC (R_(t)): 1.511 minutes; m/e: 504.32, MS (ES+): 505.32.

[0301] Compound 155:5-(2,5-Dimethoxy-phenyl)-4-[(6-methyl-4′-phenoxy-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0302] HPLC (R_(t)): 1.842 minutes; m/e: 506.29, MS (ES+): 507.29.

[0303] Compound 156:N-(5′-{N′-[3-(2,5-Dimethoxy-phenyl)-5-oxo-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-2′-methyl-biphenyl-3-yl)-acetamide

[0304] HPLC (R_(t)): 1.316 minutes; m/e: 471.56, MS (ES+): 472.56.

[0305] Compound 157:5-(2,5-Dimethoxy-phenyl)-4-[(4′-ethoxy-6-methyl-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0306] HPLC (R_(t)): 1.696 minutes; m/e: 458.21, MS (ES+): 459.21.

[0307] Compound 158:5-(2,5-Dimethoxy-phenyl)-4-[(4-methyl-3-pyridin-3-yl-phenyl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0308] HPLC (R_(t)): 1.060 minutes; m/e: 415.49, MS (ES+): 416.49.

[0309] Compound 159:5-(2,5-Dimethoxy-phenyl)-4-[(4′-hydroxymethyl-6-methyl-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0310] HPLC (R_(t)): 1.351 minutes; m/e: 444.33, MS (ES+): 445.33.

[0311] Compound 160:5-(2,5-Dimethoxy-phenyl)-4-[(3′,4′,5′-trimethoxy-6-methyl-biphenyl-3-yl)-hydrazono]-2,4-dihydro-pyrazol-3-one

[0312] HPLC (R_(t)): 1.501 minutes; m/e: 504.38, MS (ES+): 505.38.

[0313] Compound 161:4-[(6-Methyl-4′-phenoxy-biphenyl-3-yl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0314] HPLC (R_(t)): 1.890 minutes; m/e: 536.32, MS (ES+): 537.32.

[0315] Compound 162:4-[(3′-Ethoxy-6-methyl-biphenyl-3-yl)-hydrazono]-5-(3,4,5-trimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one

[0316] HPLC (R_(t)): 1.761 minutes; m/e: 488.32, MS (ES+): 489.32.

EXAMPLE 13

[0317] Compounds 163-202 were prepared by following the methods asdescribed herein. The characterization data for these compounds issummarized in Table 5 below. Compound numbers correspond to the compoundnumbers listed in table 1. TABLE 5 Characterization Data for Compounds163-202 Compound No. [M + H]⁺ R_(t) (min.) 163 445.36 1.40 164 416.291.09 165 505.30 1.56 166 507.40 1.87 167 421.24 1.65 168 472.30 1.40 169459.36 1.75 170 416.30 1.11 171 405.25 1.58 172 421.29 1.64 173 459.331.76 174 416.31 1.09 175 457.29 1.54 176 451.27 1.65 177 489.33 1.75 178446.31 1.09 179 535.35 1.52 180 435.30 1.57 181 500.39 1.30 182 577.401.90 183 491.31 1.74 184 542.41 1.49 185 529.41 1.79 186 529.36 1.81 187515.40 1.50 188 529.35 1.69 189 575.43 1.64 190 475.35 1.67 191 500.351.27 192 577.43 1.91 193 542.38 1.48 194 529.38 1.78 195 529.36 1.67 196545.41 1.61 197 527.39 1.62 198 575.42 1.62 199 431.29 1.58 200 487.361.46 201 475.33 1.37 202 487.34 1.53

[0318] While we have hereinbefore presented a number of embodiments ofthis invention, it is apparent that our basic construction can bealtered to provide other embodiments which utilize the compounds andmethods of this invention. Therefore, it will be appreciated that thescope of this invention is to be defined by the appended claims ratherthan by the specific embodiments which have been represented by way ofexample.

1. A method for inhibiting GSK-3 activity in a patient comprising thestep of administering to said patient: (a) a compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; R₂ is selected from H; alkyl;carbocyclyl; heterocyclyl; aryl; or heteroaryl; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; X is O, S or —NH; Y is N or CH; eachR is independently selected from H; alkyl; carbocyclyl; heterocyclyl;aryl; heteroaryl; or any two R groups taken together form a carbocyclyl,heterocyclyl, aryl or heteroaryl group; wherein said alkyl, carbocyclyl,or heterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂,—NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂,—S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O, ═S, ═NN(R′)₂,═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or ═NR′; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, or —N(R′)S(O)₂R′;each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″,—CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N(R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and each R″ isindependently selected from H or alkyl; or (b) a pharmaceuticalcomposition comprising said compound and a pharmaceutically acceptablecarrier, adjuvant, or vehicle; in an amount effective to inhibit GSK-3activity.
 2. A method for enhancing glycogen synthesis or lowering bloodlevels of glucose in a patient in need thereof, comprising the step ofadministering to said patient: (a) a compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; R₂ is selected from H; alkyl;carbocyclyl; heterocyclyl; aryl; or heteroaryl; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; X is O, S or —NH; Y is N or CH; eachR is independently selected from H; alkyl; carbocyclyl; heterocyclyl;aryl; heteroaryl; or any two R groups taken together form a carbocyclyl,heterocyclyl, aryl or heteroaryl group; wherein said alkyl, carbocyclyl,or heterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂,—NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂,—S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O, ═S, ═NN(R′)₂,═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or ═NR′; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, or —N(R′)S(O)₂R′;each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″,—CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N(R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and each R″ isindependently selected from H or alkyl; or (b) a pharmaceuticalcomposition comprising said compound and a pharmaceutically acceptablecarrier, adjuvant, or vehicle; in an amount sufficient to enhanceglycogen synthesis or lower blood glucose levels.
 3. The methodaccording to claim 2, wherein the patient is treated for diabetes.
 4. Amethod for inhibiting the production of hyperphosphorylated Tau proteinin a patient in need thereof, comprising the step of administering tosaid patient: (a) a compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; R₂ is selected from H; alkyl;carbocyclyl; heterocyclyl; aryl; or heteroaryl; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; X is O, S or —NH; Y is N or CH; eachR is independently selected from H; alkyl; carbocyclyl; heterocyclyl;aryl; heteroaryl; or any two R groups taken together form a carbocyclyl,heterocyclyl, aryl or heteroaryl group; wherein said alkyl, carbocyclyl,or heterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂,—NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂,—S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O, ═S, ═NN(R′)₂,═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or ═NR′; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, or —N(R′)S(O)₂R′;each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″,—CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N(R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and each R″ isindependently selected from H or alkyl; or (b) a pharmaceuticalcomposition comprising said compound and a pharmaceutically acceptablecarrier, adjuvant, or vehicle; in an amount sufficient to inhibithyperphosphorylation of Tau protein.
 5. The method according to claim 4,wherein the patient is treated for Alzheimer's disease.
 6. A method forinhibiting the phosphorylation of β-catenin in a patient in needthereof, comprising the step of administering to said patient: (a) acompound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; R₂ is selected from H; alkyl;carbocyclyl; heterocyclyl; aryl; or heteroaryl; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R. —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; X is O, S or —NH; Y is N or CH; eachR is independently selected from H; alkyl; carbocyclyl; heterocyclyl;aryl; heteroaryl; or any two R groups taken together form a carbocyclyl,heterocyclyl, aryl or heteroaryl group; wherein said alkyl, carbocyclyl,or heterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂,—NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂,—S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O, ═S, ═NN(R′)₂,═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or ═NR′; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, or —N(R′)S(O)₂R′;each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″,—CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N(R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and each R″ isindependently selected from H or alkyl; or (b) a pharmaceuticalcomposition comprising said compound and a pharmaceutically acceptablecarrier, adjuvant, or vehicle; in an amount sufficient to inhibitphosphorylation of β-catenin.
 7. The method according to claim 6,wherein the patient is treated for schizophrenia.
 8. A method forinhibiting GSK-3 activity in a biological sample, comprising the step ofcontacting the biological sample with: (a) a compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R) ₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; R₂ is selected from H; alkyl;carbocyclyl; heterocyclyl; aryl; or heteroaryl; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; X is O, S or —NH; Y is N or CH; eachR is independently selected from H; alkyl; carbocyclyl; heterocyclyl;aryl; heteroaryl; or any two R groups taken together form a carbocyclyl,heterocyclyl, aryl or heteroaryl group; wherein said alkyl, carbocyclyl,or heterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂,—NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂,—S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O, ═S, ═NN(R′)₂,═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or ═NR′; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, or —N(R′)S(O)₂R′;each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″,—CO₂R″, —C(O)R″, —C(O)N(R″)_(2, —S(O)) ₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, —NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N(R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and each R″ isindependently selected from H or alkyl; or (b) a composition comprisingsaid compound and a carrier, adjuvant, or vehicle; in an amounteffective to inhibit GSK-3 activity.
 9. A method for inhibiting Aurora-2activity in a patient comprising the step of administering to saidpatient: (a) a compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R) ₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; R₂ is selected from H; alkyl;carbocyclyl; heterocyclyl; aryl; or heteroaryl; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N (R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; X is O, S or —NH; Y is N or CH; eachR is independently selected from H; alkyl; carbocyclyl; heterocyclyl;aryl; heteroaryl; or any two R groups taken together form a carbocyclyl,heterocyclyl, aryl or heteroaryl group; wherein said alkyl, carbocyclyl,or heterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂,—NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂,—S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O, ═S, ═NN(R′)₂,═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or ═NR′; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, or —N(R′)S(O)₂R′;each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″,—CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N(R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N (R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and each R″ isindependently selected from H or alkyl; or (b) a pharmaceuticalcomposition comprising said compound and a pharmaceutically acceptablecarrier, adjuvant, or vehicle; in an amount effective to inhibitAurora-2 activity.
 10. The method according to claim 9, wherein thepatient is treated for cancer.
 11. The method according to claim 10,wherein the patient is treated for colon or ovarian cancer.
 12. A methodfor inhibiting Aurora-2 activity in a biological sample, comprising thestep of contacting the biological sample with: (a) a compound of formulaI:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; R₂ is selected from H; alkyl;carbocyclyl; heterocyclyl; aryl; or heteroaryl; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; X is O, S or —NH; Y is N or CH; eachR is independently selected from H; alkyl; carbocyclyl; heterocyclyl;aryl; heteroaryl; or any two R groups taken together form a carbocyclyl,heterocyclyl, aryl or heteroaryl group; wherein said alkyl, carbocyclyl,or heterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂,—NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂,—S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O, ═S, ═NN(R′)₂,═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or ═NR′; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, or —N(R′)S(O)₂R′;each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N (R″)₂, —NR″C(O)R″, —NR″C(O)N(R′)₂, —N(R″)CO₂R″,—CO₂R′, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N(R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N (R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and each R″ isindependently selected from H or alkyl; or (b) a composition comprisingsaid compound and a carrier, adjuvant, or vehicle; in an amounteffective to inhibit Aurora-2 activity.
 13. A method for inhibitingCDK—2 activity in a patient comprising the step of administering to saidpatient: (a) a compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; R₂ is selected from H; alkyl;carbocyclyl; heterocyclyl; aryl; or heteroaryl; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; x is O, S or —NH; Y is N or CH; eachR is independently selected from H; alkyl; carbocyclyl; heterocyclyl;aryl; heteroaryl; or any two R groups taken together form a carbocyclyl,heterocyclyl, aryl or heteroaryl group; wherein said alkyl, carbocyclyl,or heterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂,—NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂,—S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O, ═S, ═NN(R′)₂,═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or ═NR′; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N (R′)₂, —S(O)R′, or—N(R′)S(O)₂R′; each R′ is independently selected from H; alkyl;carbocyclyl; heterocyclyl; aryl; heteroaryl; or any two R′ groups takentogether form a carbocyclyl, heterocyclyl, aryl or heteroaryl group;wherein said alkyl, carbocyclyl, or heterocyclyl is optionallysubstituted with one to four substituents independently selected fromhalo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N (R″)₂, —NR″C(O)R″,—NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N (R″)₂, —S(O)R″, —N (R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″,═NN(R″)COR″, ═NN(R″)CO₂R″, ═NN(R″)SO₂R″, ═N—CN, or ═NR″; and whereinsaid aryl or heteroaryl is optionally substituted with one to foursubstituents independently selected from halo, CF₃, —R″, —OR″, —SR″,—NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″,—C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and each R″ is independently selected from H or alkyl; or(b) a pharmaceutical composition comprising said compound and apharmaceutically acceptable carrier, adjuvant, or vehicle; in an amounteffective to inhibit CDK-2 activity.
 14. The method according to claim13, wherein the patient is treated for cancer, Alzheimer's disease,restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV,herpes, psoriasis, atherosclerosis, alopecia, or rheumatoid arthritis.15. A method for inhibiting CDK-2 activity in a biological sample,comprising the step of contacting the biological sample with: (a) acompound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; R₂ is selected from H; alkyl;carbocyclyl; heterocyclyl; aryl; or heteroaryl; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; X is 0, S or —NH; Y is N or CH; eachR is independently selected from H; alkyl; carbocyclyl; heterocyclyl;aryl; heteroaryl; or any two R groups taken together form a carbocyclyl,heterocyclyl, aryl or heteroaryl group; wherein said alkyl, carbocyclyl,or heterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂,—NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂,—S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O, ═S, ═NN(R′)₂,═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or ═NR′; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, or —N(R′)S(O)₂R′;each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″,—CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N(R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and each R″ isindependently selected from H or alkyl; or (b) a composition comprisingsaid compound and a carrier, adjuvant, or vehicle; in an amounteffective to inhibit CDK-2 activity.
 16. The method according to any oneof claims 2-7, 10-11, or 14, wherein said compound or composition isadministered with an additional therapeutic agent.
 17. The methodaccording to any one of claims 1-16, wherein X is —NH.
 18. The methodaccording to claim 17, wherein R₁ is selected from H, alkyl,heterocyclyl, aryl, or heteroaryl and R₂ is alkyl, carbocyclyl,heterocyclyl, aryl or heteroaryl.
 19. The method according to claim 18,wherein each member of R₁ except H is optionally substituted with one tofour substituents independently selected from —OR, —CO₂R, —SO₂N(R)₂,—SO₂R, R₈, —CF₃, halo, —CN, or heterocyclyl optionally substituted with═O or alkyl; each member of R₂ is optionally substituted with one tofour substituents independently selected from —NO₂, —N(R)₂, —OR, —CF₃,halo, —CN, —CO₂R, —C(O)R, —C(O)N(R)₂, —N(R)C(O)R, —S(O)₂N(R)₂, —SO₂R,R⁺, or R; and R⁺ is —N(R′)₂ wherein R′ is alkyl optionally substitutedwith —OR″.
 20. The method according to claim 18, wherein each R₁ and R₂is independently selected from heterocyclyl, aryl or heteroaryl.
 21. Themethod according to claim 19, wherein each member of R₁ except H isoptionally substituted with one to four substituents independentlyselected —OH, —R₈, —O—(alkyl optionally substituted with —CO₂R₃, —OR₃ or—N (R₃)₂), —O-aralkyl, —O-carbocyclyl, —CO₂R₃, —SO₂R₃, —SO₂N (R₃)₂,—CF₃, halo, —CN, or heterocyclyl optionally substituted with ═O oralkyl; each member of R₂ is optionally substituted with one to foursubstituents independently selected from —NO₂, —N (R₃)₂, —OR₃, —O-aryl,—O-aralkyl, —O-heterocyclylalkyl, —O-(alkyl optionally substituted withR⁺ or R₁₀), —O—CF₃, —CF₃, halo, —CN, —C(O)NH₂, —C(O)N(R₁₀)₂, —CO₂R₃,—S(O)₂NH₂, —S(O)₂N (R₁₀)₂, —S(O)₂N (R₄)₂, —S(O)₂R₁₀, R₃, R₄,—NR₃C(O)R₁₀, R₁₀, R⁺, —C(O)—aryl, or aryl optionally substituted with—NR″C(O)R″, —N(R″)₂, —NO₂, —CF₃, halo, —CN, —C(O)R″, —OR″, —O-aryl, orR₁₀; each R₃ is independently selected from H or alkyl; each R₄ isindependently heteroaryl or heterocyclyl, wherein heterocyclyl isoptionally substituted with ═O, —CO₂R″ or alkyl; each R₁₀ isindependently alkyl optionally subsutituted with one or moresubstituents selected from the group consisting of —OR″, —CO₂R″,SO₂N(R″)₂, —N(R″)₂, NR″C(O)R″ and CN; and R⁺ is —N(R″)₂ wherein R′ isalkyl optionally substituted with —OR″.
 22. The method according toclaim 21, wherein R₁ is H, methyl, i—propyl, benzodioxolyl,dihydrobenzodioxinyl, thienyl, pyridyl, phenyl, dihydrobenzodioxepinyl,pyrrolyl, or benzofuranyl, wherein said benzodioxolyl,dihydrobenzodioxinyl, thienyl, pyridyl, phenyl, dihydrobenzodioxepinyl,pyrrolyl, or benzofuranyl is optionally substituted with one to foursubstituents independently selected from —OH, morpholinyl,dimethylazetidinone, —0—cyclopropyl, —O-cyclopentyl, R₈, —O-(alkyloptionally substituted with —CO₂R₃, —OR₃ or —N (R₃)₂), —O-aralkyl,—CO₂R₃, —SO₂R₃, —SO₂N (R₃)₂, —F, —CF₃, or —CN; R₂ is phenyl,dihydrobenzodioxinyl, tetrahydropyrimidinone, triazolyl, thiazolyl,hexahydropyridopyrazinone, dihydrobenzothiophene dioxide,dihydrobenzodioxepinyl, tetrahydroquinolinyl, dihydroindolyl, thienyl,pyridyl, benzyl, benzodioxolyl, carbazolyl, fluorenonyl, pyrazolyl, orcyclohexyl, wherein said phenyl, dihydrobenzodioxinyl,tetrahydropyrimidinone, triazolyl, thiazolyl, hexahydropyridopyrazinone,dihydrobenzothiophene dioxide, dihydrobenzodioxepinyl,tetrahydroquinolinyl, dihydroindolyl, thienyl, pyridyl, benzyl,benzodioxolyl, carbazolyl, fluorenonyl, pyrazolyl, or cyclohexyl isoptionally substituted with one to four substituents independentlyselected from —NO₂, pyrazolidinone, dioxolanyl, —N(R₃)₂, —O(R₃)₂,—O—CF₃, —CF₃, —F, —Cl, —Br, —CN, —C(O)N(R₁₀)₂, R₁₀, R₈, morpholinyl,—SO₂N(R₃)₂, —SO₂-morpholinyl, —SO₂-piperazinedione, —SO₂N(R₃)₂, —SO₂R₈,—CO₂R₃, —CO₂R₈, —NR₃C(O)R₃, —O-phenyl, —O-Bn, —O-pyridyl, —C(O)-phenyl,pyridyl, thienyl, benzodioxolyl, furanyl, tetrahydrofuranyl optionallysubstituted with R₈, pyrrolidinone optionally substituted with —CO₂R″,imidazolyl, —N-methylpiperazinyl, R⁺, —O-alkyl wherein alkyl issubstituted with R₁₀ or morpholinyl, or phenyl optionally substitutedwith one to four substituents independently selected from —N(R″)₂, —OR″,alkyl optionally substituted with —OR″ or —CO₂R″, benzodioxolyl,pyrrolyl, piperazinedione, —C(O)R″, —NR″CO(R″), or —OPh; and R₈ is alkylssubstituted by —OR″.
 23. The method according to claim 17, wherein saidcompound is of formula III:

wherein R₅ is H, —R₈, —O-(alkyl optionally substituted with —CO₂R₃, —OR₃or —N(R₃)₂), —O-aralkyl, —O-carbocyclyl, —CO₂R₃, —SO₂R₃, —SO₂N(R₃)₂,—CF₃, halo, —CN, or heterocyclyl optionally substituted with ═O oralkyl; R₆ is —NO₂, —N(R₃)₂, —OR₃, —O-aryl, —O-aralkyl,—O-heterocyclylalkyl, —O-(alkyl optionally substituted with R⁺ or R₁₀ ),—O—CF₃, —CF₃, halo, —CN, —C(O)NH₂, —C(O)N(R₁₀)₂, —CO₂R₃, —S(O)₂NH₂,—S(O)₂N(R₁₀)₂, —S(O)₂N(R₄)₂, —S (O)₂R₁₀, R₃, R₄, —NR₃C(O)R₁₀, R₁₀, R⁺,—C(O)—aryl, or aryl optionally substituted with —NR″C(O)R″, —N(R″)₂,—CF₃, halo, —CN, —C(O)R″, —OR″, —O-aryl, or R₁₀; each R₃ isindependently selected from H or alkyl; each R₄ is independentlyheteroaryl or heterocyclyl, wherein heterocyclyl is optionallysubstituted with ═O, —CO₂R″ or alkyl; R₈ is alkyl ssubstituted by —OR″;each R₁₀ is independently alkyl optionally subsutituted with one or foursubstituents selected from the group consisting of —OR″, —CO₂R″,SO₂N(R″)₂, —N(R″)₂, NR″C(O)R″ and CN; R⁺ is —N(R′)₂ wherein R′ is alkyloptionally substituted with —OR″; and n is 1, 2, or
 3. 24. The methodaccording to claim 17, wherein said compound is selected from any one ofthe compounds 1-290 as depicted in Table
 1. 25. The method according toany one of claims 1-16, wherein X is O.
 26. A compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:R₁ is selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; —CN; —C(O)R; —CO₂R; or —CON(R)₂; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; R₂ is selected from H; alkyl;carbocyclyl; heterocyclyl; aryl; or heteroaryl; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR,═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl orheteroaryl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; X is O, S or —NH; Y is CH; each R isindependently selected from H; alkyl; carbocyclyl; heterocyclyl; aryl;heteroaryl; or any two R groups taken together form a carbocyclyl,heterocyclyl, aryl or heteroaryl group; wherein said alkyl, carbocyclyl,or heterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂,—NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂,—S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O, ═S, ═NN(R′)₂,═N—OR′, ═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or ═NR′; andwherein said aryl or heteroaryl is optionally substituted with one tofour substituents independently selected from halo, —R′, —OR′, —SR′,—NO₂, —CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′,—C(O)R′, —C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, or —N(R′)S(O)₂R′;each R′ is independently selected from H; alkyl; carbocyclyl;heterocyclyl; aryl; heteroaryl; or any two R′ groups taken together forma carbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein saidalkyl, carbocyclyl, or heterocyclyl is optionally substituted with oneto four substituents independently selected from halo, CF₃, —R″, —OR″,—SR″, —NO₂, —CN, —N (R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″,—CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″,—N(R″)S(O)₂R″, ═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″,═NN(R″)SO₂R″, ═N—CN, or ═NR″; and wherein said aryl or heteroaryl isoptionally substituted with one to four substituents independentlyselected from halo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N(R″)₂,—NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂,—S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and each R″ isindependently selected from H or alkyl; with the proviso that when X isNH and R₁ is an unsubstituted phenyl, then R₂ is not


27. A compound of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:R₁ is selected from carbocyclyl; heterocyclyl; aryl; heteroaryl; or —CN;wherein said carbocyclyl or heterocyclyl is optionally substituted withone to four substituents independently selected from halo, —R, —OR, —SR,—NO₂, —CN, —N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R,—C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂,═N—OR, ═NN(R)COR, ═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein saidaryl or heteroaryl is optionally substituted with one to foursubstituents independently selected from halo, —R, —OR, —SR, —NO₂, —CN,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂,—S(O)₂R, —S(O)₂N(R)₂, —S(O)R, or —NRS(O)₂R; R₂ is selected from aryl;heteroaryl; carbocyclyl; or heterocyclyl; wherein said carbocyclyl orheterocyclyl is optionally substituted with one to four substituentsindependently selected from halo, —R, —OR, —SR, —NO₂, —CN, —N (R)₂, —NRC(O)R, —NRC (O)N (R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, —NRS(O)₂R, ═O, ═S, ═NN(R)₂, ═N—OR, ═NN(R)COR,═NNRCO₂R, ═NNRSO₂R, ═N—CN, or ═NR; and wherein said aryl or heteroarylis optionally substituted with one to four substituents independentlyselected from halo, —R, —OR, —SR, —NO₂, —CN, —N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRCO₂R, —CO₂R, —C(O)R, —C(O)N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, or —NRS(O)₂R; X is O, S or —NH; Y is N; each R is independentlyselected from H; alkyl; carbocyclyl; heterocyclyl; aryl; heteroaryl; orany two R groups taken together form a carbocyclyl, heterocyclyl, arylor heteroaryl group; wherein said alkyl, carbocyclyl, or heterocyclyl isoptionally substituted with one to four substituents independentlyselected from halo, —R′, —OR′, —SR′, —NO₂, —CN, —N(R′)₂, —NR′C(O)R′,—NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′, —C(O)N(R′)₂, —S(O)₂R′,—S(O)₂N(R′)₂, —S(O)R′, —N(R′)S(O)₂R′, ═O, ═S, ═NN(R′)₂, ═N—OR′,═NN(R′)COR′, ═NN(R′)CO₂R′, ═NN(R′)SO₂R′, ═N—CN, or ═NR′; and whereinsaid aryl or heteroaryl is optionally substituted with one to foursubstituents independently selected from halo, —R′, —OR′, —SR′, —NO₂,—CN, —N(R′)₂, —NR′C(O)R′, —NR′C(O)N(R′)₂, —N(R′)CO₂R′, —CO₂R′, —C(O)R′,—C(O)N(R′)₂, —S(O)₂R′, —S(O)₂N(R′)₂, —S(O)R′, or —N(R′)S(O)₂R′; each R′is independently selected from H; alkyl; carbocyclyl; heterocyclyl;aryl; heteroaryl; or any two R′ groups taken together form acarbocyclyl, heterocyclyl, aryl or heteroaryl group; wherein said alkyl,carbocyclyl, or heterocyclyl is optionally substituted with one to foursubstituents independently selected from halo, CF₃, —R″, —OR″, —SR″,—NO₂, —CN, —N(R″)₂, —NR″C(O)R″, —NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″,—C(O)R″, —C(O)N(R″)₂, —S(O)₂R″, —S(O)₂N(R″)₂, —S(O)R″, —N(R″)S(O)₂R″,═O, ═S, ═NN(R″)₂, ═N—OR″, ═NN(R″)COR″, ═NN(R″)CO₂R″, ═NN(R″)SO₂R″,═N—CN, or ═NR″; and wherein said aryl or heteroaryl is optionallysubstituted with one to four substituents independently selected fromhalo, CF₃, —R″, —OR″, —SR″, —NO₂, —CN, —N(R″)₂, —NR″C(O)R″,—NR″C(O)N(R″)₂, —N(R″)CO₂R″, —CO₂R″, —C(O)R″, —C(O)N(R″)₂, —S(O)₂R″,—S(O)₂N(R″)₂, —S(O)R″, or —N(R″)S(O)₂R″; and each R″ is independentlyselected from H or alkyl; with the proviso that: i)when X is —NH and R₂is an unsubstituted phenyl, then R₁ is not an unsubstituted phenyl; ii)when X is O and R₁ is heterocyclyl, aryl or heteroaryl, then R₂ is notheteroaryl or heterocyclyl; and iii) R₁ excludes the following groups:unsubstituted 3-pyridyl, unsubstituted naphthyl,


28. The compound according to claim 26 or 27, wherein R₂ is anoptionally substituted phenyl.
 29. The compound according to claim 28,wherein R₁ is substituted aryl or substituted heteroaryl.
 30. Thecompound according to claim 29, wherein R₁ is substituted phenyl orsubstituted pyridyl.
 31. The compound according to any one of claims26-30, wherein X is —NH.
 32. The compound according to any one of claims26-30, wherein X is O.
 33. The compound according to claim 31, wherein:R₁ is phenyl or pyridyl, wherein said phenyl or pyridyl is substitutedwith —R₈, —O-(alkyl optionally substituted with —CO₂R₃, —OR₃ or —N(R₃)₂), —O-aralkyl, —O-carbocyclyl, —CO₂R₃, —SO₂R₃, —SO₂N(R₃)₂, —CF₃,halo, —CN, or heterocyclyl optionally substituted with ═O or alkyl; R₂is phenyl optionally substituted with —NO₂, —N(R₃)₂, —OR₃, —O-aryl,—O-aralkyl, —O-heterocyclylalkyl, —O-(alkyl optionally substituted withR⁺ or R₁₀), —O—CF₃, —CF₃, halo, —CN, —C(O)NH₂, —C(O)N(R₁₀)₂, —CO₂R₃,S(O)₂NH₂, —S(O)₂N(R₁₀)₂, —S(O)₂N(R₄)₂, —S(O)₂R₁₀, R₃, R₄, —NR₃C(O)R₁₀,R₁₀, R⁺, —C(O)—aryl, or aryl optionally substituted with —NR″C(O)R″, —N(R″)₂, —CF₃, halo, —CN, —C(O)R″, —OR″, —O-aryl, or R₁₀; each R₃ isindependently selected from H or alkyl; each R₄ is independentlyheteroaryl or heterocyclyl, wherein heterocyclyl is optionallysubstituted with ═O, —CO₂R″ or alkyl; R₈ is alkyl ssubstituted by —OR″;and each R₁₀ is independently alkyl optionally subsutituted with one orfour substituents selected from the group consisting of —OR″, —CO₂R″,SO₂N(R″)₂, —N (R″)₂, NR″C(O)R″ and CN.